Hematologic malignancies are known to be associated with numerous cytogenetic and molecular genetic changes. In addition to morphology, immunophenotype, cytochemistry and clinical characteristics, these genetic alterations are typically required to diagnose myeloid, lymphoid, and plasma cell neoplasms. According to the current World Health Organization (WHO) Classification of Tumors of Hematopoietic and Lymphoid Tissues, numerous genetic changes are highlighted, often defining a distinct subtype of a disease, or providing prognostic information. This review highlights how these molecular changes can alter mitochondrial bioenergetics, cell death pathways, mitochondrial dynamics and potentially be related to mitochondrial genetic changes. A better understanding of these processes emphasizes potential novel therapies. The contribution of mitochondria in hematologic malignancies as possible targets for therapy-resistant malignancies is emerging and has been discussed in some excellent recent review articles, such as the one by Barbato and co-workers . The attIn this review article, we will focus on our current understanding of the role of mitochondria in health and disease, with a focus on their role in carcinogenesis. This will be followed by their role in hematologic malignancies, organized and discussed by the different diseases or disease groups. In each disease or disease group, we will highlight how their common genetic abnormalities are related to mitochondria and what additional therapeutic potential they hold. These genetic changes or chromosomal abnormalities are either driver mutations or have prognostic value, often related to poor prognosis or therapy resistance in a certain disease. The genes we discuss are chosen using the current literature and the latest (2017) WHO Classification of Hematopoietic and Lymphoid Tissue Malignancies book as a guide , latter Many mitochondrial changes are advantageous for cellular adaptation and proliferation, making them essential elements of cancer cell survival. These alterations, therefore, serve as potential therapeutic targets in various tumors. In this chapter, we discuss the main mitochondria-related changes concerning carcinogenesis.Mitochondria have a complex role in cellular metabolism, producing adenosine triphosphate (ATP) during OXPHOS; or from using NADH and FADH2, generated via cytoplasmic β-oxidation of fatty acids or the tricarboxylic acid cycle (TCA), latter also known as Krebs cycle. In addition, mitochondria are responsible for synthetizing lipids, amino acids, pyrimidine, and various other metabolic intermediates necessary for a functioning cell .During OXPHOS, electrons are delivered through the mitochondrial respiratory complexes, making a proton gradient across the inner mitochondrial membrane, which is the source of ATP production during this process. OXPHOS requires the presence of oxygen and often generates ROS, especially at complexes I and II . On the Mitochondrial metabolism adapts to different environmental stresses, making the cell capable of surviving under ever-changing conditions. Tumor cells, in general, have unique ways to maintain their high energy demand, with mitochondria in the center of reprogramming their metabolism . InteresBased on these findings, mitochondrial metabolism has been proposed as potential tumor therapy in addition to inhibiting glycolysis. Several inhibitors are available in targeting mitochondrial metabolic pathways or enzymes, such as the ones in the electron transport chain (ETC) , enzymes in the TCA cycle , or glutaminase (converting glutamine to glutamate)  . As discAs previously mentioned, OXPHOS is important in the production of ROS. Low levels of ROS are constantly produced in normal cells when electrons escape from the ETC, typically from complexes I and II, and react with molecular oxygen. ROS are important in intracellular signaling in low levels, such as in the response to hypoxia, growth factor-induced cell proliferation, and inflammatory response generation ,9. In adMost tumor cells, including leukemia cells, produce an increased amount of ROS due to their increased metabolism and, therefore, can be targeted with ROS-generating agents to induce apoptosis . Drugs uThe human mtDNA are multi-copied and have circular genome, approximately 16 kb in size, encoding 13 mRNA, 22 transfer RNAs (tRNAs), and two ribosomal RNAs (rRNAs). The coding regions in the mtDNA are in close connection with partial overlaps. One longer non-coding region is present in the mtDNA, referred to as the control region, with transcription promoters for both strands. The 13 encoded proteins are essential subunits of the ETC I, II, IV, and V, with the majority of the mitochondrial proteins encoded by the nuclear DNA (nDNA). The nuclear-encoded mitochondrial proteins are imported from the cytosol by two translocase complexes: the translocase of the outer membrane (TOM) and the translocase of the inner membrane (TIM) ,22,23,24POLG and POLG2 genes, encoding mtDNA polymerse γ, are involved in mtDNA replication, whereas TWNK encodes twinkle mtDNA helicase [Mitochondrial biogenesis requires coordinated nuclear and mitochondrial gene expressions for effective protein synthesis, regulated by various transcription factors. Several different proteins can directly or indirectly regulate mtDNA transcription. Most of those directly binding to the mtDNA bind to the D-loop area in the control region. The direct regulators include the mitochondrial RNA polymerase (POLRMT), transcription factors mitochondrial transcription factor A (TFAM), and mitochondrial transcription factor B1/2 (TFB1M/2M), a transcription elongation factor (TEFM), and one termination factor (mTERF1). TFAM can stabilize the mtDNA and initiate transcription, and is regulated by many intracellular regulatory proteins, such as the protein kinase A (PKA), extracellular regulated protein kinases 1/2 (ERK), or the peroxisome proliferator-activated receptor gamma coactivator 1-α (PGC-1α). A small change in PGC-1α’s concentration strongly affects mtDNA replication and transcription, and it is involved in mtDNA copy number alteration, mitochondrial dynamics, and OXPHOS regulation. Other molecules, such as signal transducers and activators of transcription 3 (STAT3) and cAMP response element-binding protein (CREB) can also bind to the D-loop area, promoting TFAM-independent gene expression. Other transcription enhancers, such as c-Jun and CCAAT enhancer-binding protein (CEBP)β, bind to different mtDNA regions ,24,25,26helicase .mtDNA is more vulnerable to insults, such as ROS production, than nDNA due to its proximity to the ROS production site, smaller amount of repair mechanisms existing, and the lack of protection by histones . ReplicaPOLRMT level have been developed, such as IMT1 and IMT1B. They successfully decrease OXPHOS and ATP production via interfering with the transcription of ETC proteins. In addition, these inhibitors reduced tumor cell growth and cell viability in ovarian and colon cancer models [Inhibitors of mitochondrial transcription at the r models . Mitochor models ,30,31.TFAM and POLG expression have been described along with increased mtDNA copy number, reversible with PGC-1α inhibition [Not only are mtDNA mutations more frequent in cancer cells, but altered mtDNA copy number has also been associated with carcinogenesis ,32,33,34hibition . In addihibition . Additiohibition . The regApoptotic pathways and their role in carcinogenesis have been well studied. It can be initiated via the extrinsic or intrinsic pathway leading to caspase activation, the central effectors of apoptotic cell death . The intUnlike apoptosis, necrosis is an unregulated process of cell death caused by severe injury. However, necroptosis, a controlled form of necrosis was described in 2005 by Degterev and co-workers , which hThe connection between the pro- and anti-apoptotic genes and carcinogenesis is well described in the literature. Increased expression of anti-apoptotic proteins, such as bcl-2 and bcl-XL are seen in untreated AML samples and advanced MDS, with higher expression associated with worse prognosis or therapy resistance. A Bcl-2 inhibitor, venetoclax (ABT-199), has been used to treat AML and relapsed Chronic lymphocytic leukemia (CLL) with 17p deletion. Similarly, altered anti-apoptotic protein mcl-1 expression was described in hematologic malignancies, such as AML, multiple myeloma (MM), and B-cell acute lymphoblastic leukemia (B-ALL). Conversely, bax level can be high with either therapy sensitivity or therapy resistance in AML. Their localization is, however, important. The cells are more sensitive to chemotherapy when bax is mainly in the mitochondria, and not in the cytosol. Interestingly, BTSA1, a bax activator, effectively suppress apoptosis in human AML xenografts ,43,44,45Necroptosis is also a potentially viable treatment for cancers that have acquired resistance to apoptotic pathways. The serine-threonine kinases RIP1 and RIP3 have been shown to induce mitochondrial fission through activation of dynamin-related protein1 (Drp1) via serine phosphorylation. Subsequently, Drp1 can interact with another regulator protein, Fis1, to induce mitochondrial fission. Ultimately, RIP1-RIP3 induced mitochondrial fission will lead to the generation of reactive oxygen species and eventually cell death via necroptosis . NecroptThe changes in mitochondrial number and morphology are described as mitochondrial dynamics . MitochoMitochondrial fission results in an increased number of mitochondria, with dynamin-related protein 1 (Drp1), a large GTPase, being the central effector protein ,51. Drp1On the other hand, mitochondrial fusion results in a decreased number, and more interconnected mitochondria, with increased oxidative capacity and MOMP ,52. Key Besides clearing dysfunctional mitochondria, mitophagy is important in various adaptive responses, where reduced overall mitochondrial mass is desirable , and is Mitochondrial fusion predominates G1/and early S-phases during the cell cycle, producing more ATP for cell growth. On the other hand, during S/G2/and M phases, mitochondrial fission is increased to provide equal distribution of mitochondria between daughter cells and to reduce OXPHOS and subsequent ROS generation and mtDNA mutations ,58,59. BBoth bioenergetic changes and apoptosis regulation via altered mitochondrial dynamics are important in carcinogenesis and thus hold tremendous therapeutic potential for various malignancies. As for the bioenergetic changes, fission generally reduces, whereas fusion increases OXPHOS efficacy ,52. AlthThe relationship between apoptosis and mitochondrial fission/fusion is complex and bi-directional. First, both Drp1 and Mfn2 are related to the pro-apoptotic protein Bax. Both proteins can be co-localized with Bax at the MOM, with Drp1 being recruited by Bax after apoptosis induction, promoting fission; and Mfn2 binding to Bax, leading to mitochondrial fusion inhibition ,53,66,672+-dependent apoptosis by limiting mitochondrial Ca2+ overload [Despite many models proving the pro-apoptotic effect of Drp-1 and mitochondrial fission, in most tumors, Drp1-mediated fission is anti-apoptotic. Drp1 expression is high in various tumors, which is associated with increased cell proliferation, metastatic potential, and poor outcome in many tumors, including AML ,78,79,80overload ,85. In aoverload .Mitophagy is also associated with apoptosis in varied ways. Excessive mitophagy induces apoptotic cell death . The PINIn sum, mitochondrial dynamics is a key regulator of apoptosis and cellular metabolism in cancer cells. Therefore, blocking Drp1-dependent mitochondrial fission, MFF, or increasing Mfn2 levels, increasing mitophagy receptor density on the mitochondria, or decreasing VDAC1 monoubiquitination are viable therapeutic options for several types of malignancies, including hematologic malignancies, as discussed later.BNIP3 and NIX, expressions were decreased in MDS, latter in the high-risk group [Mitophagy is important both in normal hematopoietic cell development and in various hematologic malignancies, discussed in detail in a recent review by Stergiou and Kapsogeorgou . In AML,sk group ,91,92,93RHOT1 and RHOT2, respectively. Miro1/2 binds to the kinesin-1/3 motor via the trafficking kinesin protein 2 (Trak2), encoded by the TRAK2 gene, moving the mitochondria towards the + end of the microtubule, called anterograde transport. The KIF5B gene encodes the kinesin-1 heavy chain. Besides Miro, additional kinesin-binding proteins, such as syntabulin (encoded by SYBU), fasciculation and elongation protein zeta 1 (encoded by FEZ1) and Ran-binding protein 2 (encoded by RANBP2), have been described, mostly in neurons and in some tumors of non-nervous system origin. For retrograde transport, Miro is forming a complex with a dynein motor and the bicaudal 2 (BiCD2) adaptor protein. There are four ways described in the literature on how mitochondrial detachment can occur from the microtubule when there is a mitochondrium-Miro-Trak2-kinesin complex present: 1. Myosin motor (MYO)-dependent binding to actin filaments 2. Mitochondrial anchoring to the microtubules via syntaphilin (SNPH), disrupting kinesin-Trak2 binding 3. Calcium-induced detachment resulting in conformational change in Miro and in the kinesin protein, and 4. The irreversible proteasomal degradation of the kinesin-1/Trak complex. All these can inhibit mitochondrial transfer along the microtubules. In addition, mitochondrial transfer along the actin filaments is typically short-range and is executed by MYOs, such as MYO19, MYO6, and MYO5. MYOs can move mitochondria both anterograde and retrograde, with the exact mechanism of mitochondrial binding unknown [Mitochondria travel in the cytosol via a microtubular network of β-tubulin or actin filaments. Mitochondria’s microtubular transport primarily uses Rho GTPases, such as Mitochondrial receptor protein 1 and 2 (Miro1/2), encoded by  unknown ,52,94,95TRAK1, MIRO1/2, KIF5B, RANBP2, or FEZ1, are associated with enhanced cell proliferation and invasion and chemotherapy resistance in some solid tumors. SNPH is typically downregulated in cancers, with its depletion or loss resulting in a worse prognosis and enhanced cell invasion. On the other hand, we have minimal knowledge on how the actin-MYO mitochondrial trafficking is altered in cancer cells. Furthermore, more research is needed to clarify how mitochondrial trafficking is affected in hematologic malignancies [Excellent recent review articles are available on the changes in mitochondrial trafficking in cancer ,95,96, wgnancies . As discPrimary mitochondrial issues in hematologic diseases, such as in Pearson syndrome or some congenital neutropenias, are rare ,99. In aMDSs are clonal hematopoietic malignancies predominating in people above 70 years. It is characterized by ineffective hematopoiesis leading to cytopenias and can transform to AML in approximately 30–40% of the cases. The etiology of MDS is unknown in 85% of the cases. Numerous cytogenetic alterations, hereditary or acquired mutations in somatic and mitochondrial genes, hereditary genetic syndromes, or environmental factors are responsible for developing the disease .RUNX1, CBFB-MYH11, PML-RARA, BCR-ABL1 etc. Also, there is a separate category for myeloid neoplasms with germline mutations, including DDX41 and CEBPA, amongst others. In addition, several genes are highlighted that provide prognostic information both in AML and MDS [AML is a phenotypically and genetically heterogeneous group of hematological malignancies characterized by clonal expansion of myeloid precursors with diminished capacity for differentiation . AML rep and MDS . AdditioTP53 mutation/alteration. Acquired somatic molecular mutations are seen in 80–90% of MDS patients, which can be grouped by gene function as follows [(1)TET2), additional sex comb-like genes (ASXL1), DNA-methyltransferase family (DNMT3A), isocitrate dehydrogenases (IDH 1/2), enhancer of zeste homolog 2 (EZH2)Epigenetic regulators and chromatin remodeling factors: methylcytosine dioxygenases of the ten eleven translocated family ((2)SF3B1, SRSF2, U2AF1mRNA splicing factors: (3)RUNX1, TP53Transcriptional factors: (4)NRAS, KRASSignaling molecules: (5)STAG2Cohesin complex: The most common genetic alterations in MDS/AML are clonal chromosomal abnormalities, found in approximately 30–80% of patients. In the remaining 20–70% of patients with normal karyotype, point mutations, microdeletions, amplifications, epigenetic changes, or copy number neutral loss, such as uniparental disomy provide the genetic basis of the disease . The com follows :(1)EpigeTET2, SF3B1, ASXL1, SRSF2, DNMT3A, TP53, EZH2, IDH1/2, NRAS, BCOR, and RUNX1; and approximately further 30 genes are altered in about 1% of patients. Most of these mutations carry a poor prognosis, except for SF3B1. It is to note that some elderly (70–80 years old) people carry one or more of these mutations, typically DNMT3A, TET2, or ASXL1, and less often JAK2, PPM1D, SF3B1, SRSF2, or TP53, with no hematologic malignancy, and the term “clonal hematopoiesis of indeterminate potential” was established to describe this condition [The most common mutations present in more than 5–10% of the patients include ondition ,102,110.Besides the mutations mentioned above in the context of MDS and post MDS AML, some additional mutations and chromosomal rearrangements have been described in the pathogenesis of AML ,112. TheSIRT3-mediated OXPHOS has been described along with increased mitochondrial fitness and ROS levels, leading to drug resistance. In addition, PDH and α-KGD inhibitors, IACS-010759 and Venolex, could re-sensitize AML cells to chemotherapy [Metabolic changes are numerous in AML and have been reviewed in excellent recent articles from Barbato and co-workers and Panuzzo and co-workers ,117. HerFIS1 knock-down resulted in cell cycle arrest, loss of self-renewal and attenuated myeloid cell differentiation [FLT3-internal tandem duplication (ITD) inhibition therapy in AML [FIS1 expression likely to be chemotherapy-resistant and were more frequently M0/M1 FAB subtypes [CBL exon deletion and RUNX1 mutation, promoting dysplasia and impaired granulopoiesis [Overexpression of mitochondrial fission receptor Fis1-mediated mitophagy was found to be essential for AML cell proliferation and differentiation in vitro. In the same model, depleting Fis1 via shRNA-mediated ntiation . In addiy in AML . In a prsubtypes . Similaropoiesis . Additioopoiesis . Interesopoiesis ,123.Here we aim to summarize the relationship between different genetic mutations, mitochondrial metabolism, mitochondrial dynamics, and the development of MDS/AML in selected genes. It is to note that there is a significant overlap in genetic alterations in these two diseases and that some genetic alterations are also present in other hematologic malignancies.Epigenetic regulation or modification means different mechanisms that alter gene expression without alterations in nucleotide sequence. The two main mechanisms of epigenetic regulation are DNA methylation and histone modifications. The interaction between DNAm, mitochondria, and transcriptional factors in hematologic malignancies are summarized in DNAm mechanisms. DNAm entails the conversion of cytosine to 5-methylcytosine (5mC) to the 5th carbon of the ring of cytosine, predominantly due to the DNA methyltransferase (DNMT) enzyme transferring a methyl group from S-adenosylmethionine (SAM). This conversion is usually found within CpG dinucleotide sites, regions of the DNA in which a cytosine nucleotide is immediately followed by a guanine nucleotide in a linear sequence in the 5′ to 3′ direction [DNAm and related genes. Such epigenetic DNA modifications occur in intronic, exonic and intergenic regions [DNMT3A), isocitrate dehydrogenase 1/2 (IDH1/IDH2), and ten-eleven translocation superfamily 2 (TET2) play an important role in the pathogenesis of a large proportion of MDSs and AMLs, with possible common targeted therapies in the future [irection . TET enzirection . DNAm an regions . They ar regions ,127. Wit regions ,129. Thi regions , particu regions . Dysregue future .DNAm genes and mitochondrial genomics. Cells harboring distinct mitochondrial haplogroups, meaning that they possess identical nuclei with different mtDNA or mtDNA polymorphisms , have been shown to have different nuclear DNA (nDNA) methylation patterns [patterns ,135,136.patterns ,138. Thepatterns ,139,140.patterns : succinapatterns . Additiopatterns .The methylation status of the mtDNA. For a long time after the 1970s it was a debated whether methylation occurs in the mtDNA or not [A or not ,144,145 A or not ,146.Mitochondrial respiratory complex dysfunction and DNAm. Notable data are available from studies, where rotenone-induced complex I dysfunction resulted in global changes in DNAm levels in rats, human cybrid cells, and the change was also seen in the offspring of a mouse model [se model ,149,150.se model ,151.Histone. Both DNAm and histone modifications, such as deacetylation, acetylation, and methylation are associated with regulation of chromatin structure and gene expression. Histone deacetylases (HDAC), which remove acetyl groups from the histones, result in more closed chromatin structure, inhibiting or decreasing gene transcription. HDAC enzymes have been found over-expressed in various malignancies, including AML. However, HDAC inhibitors have limited efficacy as single agents in some studies [ studies ,152,153. studies . The mtDIDH. The human genome has five IDH genes that encode three distinct IDH enzymes, whose activities are either NADP+ (IDH1 and IDH2) or NAD+ (IDH3) dependent. In MDS/AML, only IDH1 and 2 have a pathogenetic role. IDH1 is cytoplasmic, whereas IDH2 is a mitochondrial enzyme. The two enzymes’ main biological functions are related to the biosynthesis of essential metabolites of the TCA/Krebs cycle that, in connection with the pentose phosphate pathway, is mainly responsible for the generation of NADPH, the main component of the cellular redox homeostasis [eostasis .IDH and mitochondria and the pathogenetic role of IDH2 mutation. IDHs contribute to mitochondrial metabolism, although they have an indirect but crucial effect on DNA methylation via influencing enzyme activities through the products of their activity. In mitochondria, the reductive carboxylation of α-ketoglutarate to isocitrate by IDH2 consumes mitochondrial NADPH, with citrate/isocitrate transported to the cytoplasm, where these metabolites can be oxidized to produce cytosolic NADPH. The reversed process can be used to produce mitochondrial NADPH. Mutant IDH2, on the other hand, catalyzes the reductive conversion of α-KG to 2-dihydroxyglutarate with concomitant oxidation of NADPH to NADP+. This oxidative microenvironment plays a crucial role in the altered metabolism of clonal hematopoietic cells. It is suggested that 2-dihydroxyglutarate (2-DHG) could represent the oncogenic mediator in leukaemogenetic processes. α-KG is a cofactor of many deoxygenases involved in regulating key biological processes, such as nucleic acid repair, hypoxic response, chromatin modification, and fatty acid metabolism. In contrast, 2-DHG has the opposite effect as it acts as an inhibitor of these processes. 2-DHG is a competitive inhibitor of histone demethylases, and it has an influence on hypoxia-inducible factor (HIF) prolyl hydroxylase  and the proapoptotic effect of arsenic trioxide (ATO) by themselves or in combination with each other [IDH mutations can act as therapeutic targets for bcl-2 inhibitors. IDH1 and 2-mutant primary human AML cells were more sensitive than IDH1/IDH2-WT AML cells to ABT-199, a specific BCL-2 inhibitor, by inhibiting cytochrome c oxidase in the mitochondrial ETC [ch other . Besidesrial ETC . In addirial ETC .IDH2 inhibition. At the cellular level, the main effect of enasidenib is to induce cell differentiation without apoptosis induction. In addition, it reduces the 2-DHG level markedly. Co-occurrence of mutations at the MAPK and RAS pathways level was associated with reduced clinical response to enasidenib. Furthermore, enasidenib improved outcomes in an in vivo human AML xenograft model [TET2, FLT3-ITD, and IDH2-R140Q; thus, triple-transformed leukemia, showed tumor sensitivity both to 5-azacytidine and to IDH2 inhibitor enasidenib. The combined treatment with these two drugs resulted in a marked potentiation of the antileukemic effect, with a pronounced decrease of leukemic blasts and with their differentiation and, particularly, with a decrease of mutant allele burden and progressive recovery of normal hematopoiesis from non-mutant stem-progenitor cells [ft model . These oor cells ,172.IDH2 inhibition in clinical trials. Both monotherapy with enasidenib and combination therapy with enasidenib and 5-azacytidine vs. 5-azacytidine alone showed high response rates in IDH2 mutant AML patients [IDH2 mutation following allogenic stem cell transplantation, who had overall good response rate and an improved median of survival [IDH2-mutated MDS: the best result, which was a 100% response, was achieved in hypomethylating-agent naive patients. Interestingly, the clearance of IDH2 mutation was observed in some patients [patients ,174,175.survival . Efficacpatients .IDH2 and mitochondrial dynamics. Besides its already complex role in cellular metabolism, loss of IDH2 was associated with increased mitochondrial motility and fission, the latter via Drp1 activation and expression in in-vitro and in vivo tumor models. These changes resulted in greater tumor cell movements. The exaggerated mitochondrial trafficking was induced by ROS and subsequent hypoxia-inducible factor-1α stabilization [IDH2-mutations.lization . TargetiThe TET enzyme superfamily. The three enzymes of the TET family  identified in humans are evolutionarily conserved dioxygenases. Different TET enzymes exhibit distinct expression patterns in vivo, with TET1 being mainly expressed in embryonic stem cells. TET2 and TET3 are more ubiquitous, with TET2 expression predominating in various differentiated tissues, especially in hematopoietic and neuronal lineages [lineages .The physiological role of TET2 and its contribution in hematologic malignancies. TET enzymes are one of the homeostatic links between intracellular metabolism and epigenetic gene regulation [gulation . TET diogulation ,182. As gulation .TET isoforms in mitochondria. Despite unknown mechanisms of translocation to the mitochondria, TET1 and TET2 enzymes have been found to be present in mouse neuronal mitochondria, for example in the cerebellum and Purkinje cells of aged animals [ animals . Moreove animals ,185. TETAnimal models. Several studies have examined TET2 inactivation in mice: its deletion leads to hematopoietic defects, including enhanced HSC self-renewal and myeloid expansion, correlating with global loss of 5-hmC in primitive hematopoietic populations [ulations ,187,188.Factors influencing TET2 function. It was recently described that restoring TET function via inducible shRNA model of TET-induced AML, or through vitamin C administration, the latter being a cofactor for α-KG dependent dioxygenases reverses leukemogenicity induced by the mutant TET protein [TET2-mutated AML show significant overlaps with those found in IDH1/IDH2 mutated patients. It is to note that IDH1/IDH2 and TET2 mutations are mutually exclusive in AML [ protein . These re in AML  but signe in AML ,191.TET2 and hematopoiesis. TET2 has pleiotropic roles in hematopoiesis, including stem-cell self-renewal, lineage commitment, and terminal differentiation of specific lineages. The TET2 gene is highly expressed in HSCs and progenitor cells and is downregulated with differentiation. Several studies on mouse models proved that TET2 acts as a tumor suppressor as well [ as well ,192,193.The role of TET mutations in MDS and AML. TET2 alteration was one of the most prevalent genetic abnormalities (25–35%) identified in MDS [TET2 status can be associated with a better response to the demethylating agent azacitidine [TET2 mutations is higher in secondary than in de novo AMLs. In addition, TET2 genetic alterations could be associated with adverse outcomes in cytogenetically defined subgroups of AML patients [d in MDS ,196,197.d in MDS . Neverthpatients ,200,201.TET2 mutations in other hematologic and non-hematologic malignancies. Somatic alterations in TET2, including deletions and missense, nonsense and frameshift mutations, have been identified in 10–26% of MPN patients [TET2 were identified in 2–20% of classical MPNs, including polycythemia vera, essential thrombocytosis and primary myelofibrosis [TET2 mutations are only seen when the disease progresses to acute leukemia [TET2 mutations were associated with acute blastic transformation [TET2 mutations were identified in 20% of mastocytosis, mostly in aggressive forms of the disease [TET2 mutations have been also found in 30% of patients with blastic plasmacytoid dendritic cell neoplasms [TET2 mutations have been also identified in mature B-cell (2%) and T-cell (11.9%) lymphomas [TET2 mutations are frequently associated with DNA methyltransferase 3A mutations [IDH2 mutations [TET2 mutations have also been detected in a small number of solid tumors, such as in prostate cancers [patients ,203. Acqfibrosis ,204,205.leukemia ,207. In ormation . Additio disease ,210. Moreoplasms ,211. TETymphomas ,213, in ymphomas , in mantymphomas , and difymphomas . Interesutations , and IDHutations . TET2 mu cancers .TET2 in AML/MDS therapy. TET2 gene alterations were anticipated to predict an increased response to hypomethylating agents and this predictive effect was explored in several cohorts of high-risk MDS, AML with low blast counts, and severe CMML patients [patients ,222,223.patients ,221.The DNMT enzyme family. The DNMT family, including DNMT1, DNMT3A, and DNMT3B encode methyltransferases that catalyze DNA methylation that involves adding a methyl group to the carbon-5 position of cytosine in CpG dinucleotides, leading to the formation of 5-methylcytosine (5-mC). DNMT3A and DNMT3B are involved in de novo DNA methylation, whereas DNMT1 plays a role in the maintenance of DNA methylation [hylation . DNMT3A hylation .DNMT isoforms in the mitochondria. DNMT1 has been observed to translocate into the mitochondria and interact with the mtDNA in the matrix of some tissues, such as mouse embryonic fibroblasts, human colon cancer cells [er cells , and humer cells . The preer cells ,228,229.DNMT3A and leukemogenesis. The mechanism of leukemogenesis by DNMT3A is not entirely clear; however, studies have shown that heterozygous DNMT3A ablation in mice leads to an expansion of the hematopoietic stem cell pool [DNMT3A mutation, just as mutations in other epigenetic regulators, do not necessarily lead to frank leukemic transformation on their own but rather create a premalignant state that lays the ground for malignancy. It has recently been reported that mutant DNMT3A (R882H) interacts with the Polycomb repressive complex 1 (PRC1) in order to silence genes, suggesting that PRC1 activity could be an attractive target in DNMT3A-mutant tumors [ell pool . The fort tumors .The role of DNMT3A mutations in MDS and AML. DNMT3A mutations occur in 30–35% of AMLs with normal karyotype, 10% of MDSs, and 20% of T-lineage acute lymphoblastic leukemia [DNMT3A mutations result in loss of function, and can be present in pre-leukemic hematopoietic stem cells, which can remain in the tumor cells after transformation to MDS or AML [DNMT3A mutations are associated with poor prognosis and decreased overall survival [DNMT3A mutations have a shorter OS and higher risks of leukemic transformation [DNMT3A mutations have been observed in non-leukemic T-cells from AML patients as well and in normal elderly individuals with no signs of leukemia [leukemia ,233,234.S or AML ,236. DNMsurvival . MDS patormation ,239. Addleukemia .DNMT3a in MDS/AML therapy. DNMT3A mutations are associated with a positive response to DNA methyltransferase inhibitors (a.k.a. DNA demethylating agents), namely azacitidine, decitabine and guadecitabine [citabine ,241. Thecitabine .ASXL superfamily. The ASXL superfamily of genes and the encoded proteins consist of three members, namely ASXL1, ASXL2 and ASXL3. They are human homologs of the Drosophila Asx gene, encoding epigenetic scaffolding proteins that are involved in the regulation or recruitment of the polycomb-group repressor complex (PRC) and trithorax-group (trxG) activator complex, participating in epigenetic regulation and histone modification [ASXL1 directly interacts with various protein-coding genes, such as BAP1, KDM1A (LSD1), NCOA1, and nuclear hormone receptors, such as retinoic acid receptors, estrogen- and androgen receptors. The loss of the ASXL1 gene is associated with leukemoid transformation and increased self-renewal in hematopoietic cells [fication . ASXL1 dic cells .The role of ASXL1 in mitochondrial and endoplasmic reticulum function. A recent publication reported a significant mitochondria–endoplasmic reticulum deficiency in a leukemia cell line carrying ASXL1 mutation. This deficiency was related to decreased number of matrix granules, mitochondria-associated endoplasmic reticulum membrane (MAM), and mitochondrial-derived vesicle (MDV) precursors, which are implicated in the regulation of cell death pathways via mitophagy and intracellular Ca2+ concentration changes. These cells are also thought to have increased mitochondrial respiration and defective mitophagy [itophagy .ASXL1 mutations in hematologic malignancies. Nonsense point mutations or frame-shift mutations of ASXL1 occur in hematological malignancies, such as MDS, MPNs, MDS/MPNs, AMLs and CLL [ASXL1 is mutation rate in CLL [ASXL1 mutations are independent adverse prognostic factors both in overall and leukemia-free survival. In addition, ASXL1 mutations are associated with shorter overall survival in CMML patients [ASXL1 mutations were more frequently found in male [ASXL1 mutations are frequently seen with other gene alterations, such as with EZH2 IDH1/2, RUNX1, and TET2 [ASXL1 mutations are associated with poor prognosis in many cases [ and CLL ,245,246.e in CLL . In MDS,patients ,248,249. in male ,253,254, in male , and in and TET2 ,256, mosny cases .ASXL1 in MDS and AML therapy. Leukemic cells with ASXL1 mutation have been shown to overexpress anti-apoptotic Bcl-2 and have increased global cytosine methylation levels. It is not surprising that these cells were sensitive to both the Bcl-2 inhibitor venetoclax and the DNMT-inhibitor azacytidine [cytidine . In addicytidine .EZH2 and carcinogenesis. Enhancer of zeste homolog 2 (EZH2) is an epigenetic modulator, part of the polycomb repressive complex 2 (PRC2) that can suppress gene expression via histone 3 (H3K27me3) di- or trimethylation. In addition, EZH2 methylates non-histone proteins, such as the transcription factor GATA4, and can activate downstream genes in a PRC2-independent manner, contributing to its complex effect on cells. Mutation or altered expression of EZH2 has been linked to various tumors, including hematologic malignancies and solid tumors, such as breast cancer, esophageal cancer, gastric cancer, and anaplastic thyroid carcinoma. Interestingly, both increased and decreased EZH2/PRC2 functions are associated with carcinogenesis. With increased function, EZH2 silences genes that promote differentiation and restrain proliferation. As a tumor suppressor, loss of EZH2 accelerates Ras-driven neoplastic processes and can amplify Akt and ERK activation. In JAK2-V617F transgene mice with concurrent EZH2 knockout, a synergistic effect with very high platelet and neutrophil count, accelerated myelofibrosis, and reduced survival was described. Additionally, PRC2 is suppressed in T-cell acute lymphoblastic leukemia (T-ALL) by NOTCH1 signaling, resulting in loss of H3K27me3 repression as part of leukemogenesis. In CML, EZH2 overexpression is induced by BCR-ABL1 via signal transducer and activator of transcription (STAT) 5 phosphorylation [rylation ,264,265.EZH2 in malignancies. The type of EZH2 alteration is different in different tumor types. Solid tumors often overexpress EZH2, whereas hematologic neoplasms show a more diverse picture of how EZH2 is altered. Gain-of-function mutations, promoting H3K27me3 and subsequent gene suppression, have been described in germinal center-type diffuse large B-cell lymphomas (30%) and follicular lymphomas (20%). Gain of copy-number, as part of gains of chromosome 7 (including the 7q36.1 region), has also been described in follicular lymphomas, resulting in the same overall effect as the gain-of-function mutations in these patients. In patients with various B-cell lymphomas, high-risk MDS, and AML, overexpression of EZH2 is the most common. Interestingly, loss-of-function mutations have also been described in MDS (6%), MDS/MPN (10–12%), and myelofibrosis (13%). [EZH2 [EZH2 mutations are associated with inferior overall survival in myeloid malignancies, with no increased rate of AML transformation in MDS patients [EZH2 mutations in either of the mutated hotspots [s (13%). ,264,266.patients ,267. In patients . Also, ihotspots . Loss ofhotspots .EZH2 and mitochondria. EZH2 alters apoptotic pathways, with no data on its effect on mitochondrial dynamics. In glioma cells, its downregulation results in apoptosis and cell cycle arrest in the G0/G1 phase via cytochrome c release [ release . Similar release . On the  release . In cont release . Neverth release , and inh release . Moreove release ,275.EZH2 as targeted therapy. Patients with a gain of function mutations, or increased copy-number have been proposed to be ideal candidates for EZH2 inhibitor treatment. EZH2 inhibitors have been tested in clinical trials in various malignancies, including myeloid and lymphoid neoplasms, listed in more detail in the review of Duan and co-workers [-workers ,266, wit-workers ,277.SF3B1, SRSF2, ZRSR2 or U2AF1/2, occur in approximately 50% of MDSs and are currently intensively examined for their therapeutic relevance [RNA splicing or alternative splicing is where mature RNA is formed from pre-messenger RNA (pre-mRNA) through intron removal and exon splicing. Alternative splicing increases the transcriptomic and proteomic complexity by generating distinct RNA isoforms with different functions than the other products from the same gene. Alternative splicing can contribute to carcinogenesis when dysregulated ,279. Miselevance ,282,283.Alternative splicing is also regulated by epigenetic changes ,285. HisSF3B1 encodes a subunit of the splicing factor 3b complex. SF3B1 disrupts the usage of thousands of splice junctions, leading to altered expression of hundreds of genes [SF3B1 mutations are seen in 57–75% of patients with refractory anemia with ring sideroblasts (RARS) and 6–18% of patients with MDSs without ring sideroblasts [of genes . SF3B1 mroblasts ,289.SF3B1 in mitochondrial metabolism. The mutated SF3B1 downregulates genes essential to various mitochondrial pathways, including ACACA (acetylcoenzyme A carboxylase α) and RGL1  genes. SF3B1-mutated RARS have abnormal splicing of the ABCB7 gene in the mitochondria, which leads to deficiency of the ABCB7 protein, resulting in mitochondrial iron overload, reduced heme synthesis, and ineffective erythropoiesis [SF3B1-mutated MDS is associated with thrombocytosis, increased ring sideroblasts, fewer cytopenias, lower blasts percentage, and are associated with a favorable prognosis [opoiesis ,290. SF3rognosis .Metabolic effect of SF3B1 mutation. A recent in vitro study showed that SF3B1 mutated cells expressed less mitochondrial complex III gene, resulting in decreased cellular respiration and reduced citric acid cycle metabolites. In addition, further misspliced and downregulated mitochondrial metabolic enzymes, such as dihydrolipoamide S-succinyltransferase (DLST) and methylmalonyl-CoA mutase (MUT), were noted. This metabolic reprogramming bears a particular relevance in MDSs with ring sideroblasts (MDS-RS) with SF3B1 mutation [mutation .SRSF2, encoding the serine/arginine-rich splicing factor 2, is critically involved in splice site selection, spliceosome assembly, and constitutive and alternative splicing [SRSF2 mutations are stable during disease evolution in MDS, suggesting that they may play a role in disease initiation. SRSF2 mutations are seen in 11–15% of patients with MDS, frequently co-existing with RUNX1, IDH1, IDH2, and ASXL1 mutations [splicing . SRSF2 mutations , and conutations ,293.SRSF2 and mitochondria. In mammalian cells, nutrients and growth factors signal through an array of upstream proteins to regulate the mTORC1 growth control pathway. SRSF2 gene function impacts the mTORC1 pathway, and mitochondrial stress influences mTORC1 signaling as well [ as well .U2AF1 gene encodes the U2 auxiliary factor, facilitating the binding of U2 snRNP to the pre-mRNA branch site. Recurrent mutations of the U2AF1 gene occur in 9% of patients with MDS. The prognostic impact of U2AF1 mutations and the exact mechanism of U2AF1S34F mutation confers a clonal growth advantage in MDS remain unclear [The  unclear ,295. FOX unclear .The main effects of the transcription factors discussed are summarized in All RUNX proteins contain the runt-homology domain (RHD), which is responsible for DNA-binding and interaction with a common heterodimeric partner, CBFb . The fusRUNX1 in mitochondria. In a mouse model with both RUNX1 mutation and CBL exon deletion increased Drp1-dependent mitochondrial fission and ROS production in the tumor cells, leading to impaired granulopoiesis dysplasia and an overall MDS phenotype. These changes were reversible with Drp1 inhibition, making it a promising therapeutic candidate in MDS patients harboring RUNX1 mutation/RUNX1/RUNX1T1 fusion gene [ion gene .RUNX1 in AML.RUNX1 and CBFB are frequent targets of chromosome abnormalities in human AML and ALL. Core inding factor (CBF) leukemia subtypes, which includes leukemias harboring fusion genes CBFB/MYH11 or RUNX1/RUNX1T1, are associated with younger age and range from 20% in pediatric to less than 5% in older AML patients [RUNX1 are detected in approximately 3% of pediatric and 15% of adult de novo AML patients. In cytogenetically normal cases, the presence of RUNX1 mutations is associated with poor prognosis [patients . Moreoverognosis ,311,312.RUNX1 in MDS. Several studies reported somatic mutations in RUNX1 in patients with primary MDS, therapy-related MDS (t-MDS), and AML from MDS progression [RUNX1 mutations in MDS are distributed throughout the gene, affecting both major functional domains. RUNX1 is one of the most frequently mutated genes in MDS, accounting for roughly 10% of the cases [RUNX1 mutations and shorter survival [gression ,319,320.gression ,321. RUNhe cases . In primsurvival .TP53 and apoptosis inhibition, mutant p53. TP53 is a tumor suppressor gene encoding the tumor suppressor protein p53. When p53 forms a homotetrameric transcription factor, it directly regulates about 500 target genes, resulting in various changes, including cell cycle arrest and cell senescence, DNA repair, metabolic adaptation, and apoptosis. Of note, there is significant cross-talk between TP53 and MYC. Additionally, p53 induces apoptosis and autophagy in a transcription-independent way, interacting with other proteins in the cytoplasm [TP53 is an unusual tumor suppressor. In contrast to other tumor suppressors, such as RB and PTEN, where protein expression is significantly deceased or lost, mutant p53 expression can be high compared to the wild type (WT) p53 [ytoplasm . The indytoplasm . In the ytoplasm . In addiytoplasm ,327. TP5(WT) p53 . The mut(WT) p53 .TP53 and metabolism. Although inhibiting apoptosis is an important part of TP53-related carcinogenesis, it also greatly impacts cellular metabolism and mitochondrial dynamics. This is supported by the in vivo mouse model, where the animals lacking the critical effectors of p53-apoptosis do not develop tumors spontaneously, as the TP53-deficient mice [TIGAR) lowers the levels of reactive oxygen species (ROS) and fructose-2,6-biphosphate, thereby further inhibiting glycolysis. P53 further represses glycolysis by the transcriptional inhibition of PFKFB3 and PFKFB4 genes, which reduce fructose-2,6-bisphosphate expression. In addition, p53 inhibits the pentose phosphate pathway (PPP) by direct binding to glucose-6-phosphate dehydrogenase (G6PD), and it also inhibits the expression membrane-bound lactate transporter. OXPHOS is induced by p53, which represses the transcription of pyruvate dehydrogenase kinase 2 (PDK2), a negative regulator of pyruvate dehydrogenase (PDH) that converts pyruvate to acetyl-CoA, a primary substrate in the TCA cycle. OXPHOS is enhanced by p53 via the activation of mitochondrial glutaminase 2 (GLS2), catalyzing the hydrolysis of glutamine to glutamate. Additionally, p53 suppresses fatty acid synthesis and enhances lipid synthesis, unfavorable for tumor cells. Interestingly, TP53 with a gain-of-function mutation promotes glycolysis [TP53 are more aggressive. These effects also represent possible therapeutic targets.ent mice ,328. Theycolysis ,330,331.TP53 and mitochondrial dynamics. Supporting cellular senescence, p53 promotes the formation of highly interconnected mitochondria by blocking fission protein Drp1 translocation to the mitochondria. This translocation inhibition can occur via inhibitory phosphorylation of Drp1 at the Ser637 site. This inhibitory action is part of its tumor suppressor effect. P53-dependent Protein kinase A (PKA) activation has also been linked to mitochondrial elongation [ongation ,333. On ongation . In pationgation .TP53 in tumors.TP53 mutations have long been described in the literature along with Li-Fraumeni syndrome, where the patient carries a heterozygous mutation of the TP53 genes, resulting in the development of multiple malignancies [TP53, resulting in impaired function. These mutations depend on the tumor cell type, with many malignancies harboring various possible TP53 mutations [gnancies ,337. Mosutations .TP53 in hematologic malignancies. In MDS patients, TP53 mutations, especially mutli-hit TP53 mutations, are associated with high-risk disease, rapid transformation to AML, and therapy resistance. On the other hand, patients with monoallelic TP53 mutations had a higher incidence of other genetic mutations, including genes, such as TET2, SF3B1, ASXL1, RUNX1, SRSF2, JAK2, BCOR and CBL [TP53 mutations occur in about 5–10% of patients, with a higher incidence in the t-AMLs, and are associated with therapy resistance and short overall survival [TP53-aneuploidy showed inferior outcomes [TP53 mutations are frequently seen in lymphoid malignancies, such as in DLBCL (20–25%) and mantle cell lymphoma (25%) [TP53 mutations and treated with R-CHOP had inferior outcomes [TP53 and MYC expressions can co-exist, with a significant cross-talk between the two pathways, accelerating each other’s effect. Given that both TP53 and MYC alterations are associated with worse outcomes, their co-existence results in particularly poor prognosis [TP53 alterations include monoallelic deletion as part of deletion of chromosome 17p (del17p) (~8%), monoallelic mutations (~6%), and biallelic inactivation (~4%), associated with high-risk disease [ and CBL . In AML,survival ,340. In outcomes . Furtherma (25%) ,343. Addoutcomes ,343. In rognosis . In mult disease .RAS proto-oncogenes, such as HRAS, NRAS, and KRAS, encode small GTPases and are frequently seen in various tumors. They exist in GTP-bound active, and GDP-bound inactive forms. When activated, they modulate a wide range of gene transcription. Oncogenic RAS mutations commonly result in amino acid substitutions, locking Ras proteins in a GTP-bound and constitutively active state [ve state . Ras oveve state . Interesve state ,346. TheRAS-induced metabolic changes. Ras and Myc similarly suppress OXPHOS and enhance glycolysis, described in various tumors [s tumors . Ras, hos tumors . The sigs tumors . In addis tumors .RAS-induced changes in mitochondrial dynamics. Increased Ras expression and Erk activation leads to enhanced Drp-1-dependent mitochondrial fission, which was necessary for Ras-induced carcinogenesis in preclinical models [l models ,80. Intel models .RAS in hematologic malignancies. Both AML and MDS frequently harbor RAS mutations, with NRAS predominating [NRAS mutations are frequently associated with AML progression from MDS [NRAS mutations in primary AML did not influence the prognosis of patients. However, a co-existent USAF1 mutation in AML with RAS mutation, however, was related to chemotherapy resistance [minating ,349. Altfrom MDS , severalsistance . Targetisistance , along wBCR-ABL1 genes, also termed the Philadelphia chromosome. Although chromosomal abnormalities do not characterize most myeloproliferative disorders, other potential abnormalities include del(9p), del(13q), del(20q), gains of chromosome 8 or 9; and those more suggestive of primary myelofibrosis include der(6)t. In addition, the presence of various genetic mutations are common, and include mutations in Janus kinase 2 (JAK2), and less frequently calreticulin (CALR) or thrombopoietin receptor . The most prevalent alteration in JAK2 is a phenylalanine replacement of valine at position 617, commonly referred to as JAK2V617F. Other mutations in exon 12-15 of JAK2 also occur to a lesser extent [As the name suggests, myeloproliferative neoplasms (MPNs) are characterized by overproduction of a specific cell line, such as white blood cells, red blood cells, and platelets. The quintessential disorder in this category of hematologic disorders is chronic myeloid leukemia (CML). However, it also includes polycythemia vera (PV), essential thrombocythemia (ET), primary myelofibrosis (PMF), chronic neutrophilic leukemia (CNL), chronic eosinophilic leukemia (not otherwise specified) (CEL), and other unclassifiable myeloproliferative neoplasms. The chromosomal abnormality associated with CML is t, resulting in the fusion of clude dert oncogene on chromosome 9 to the Breakpoint Cluster Region (BCR) on chromosome 22 results in the fused BCR-ABL1 gene. The following protein product induces neoplastic proliferation through deregulated tyrosine kinase activity. The combined BCR-ABL1 product loses its regulatory activity and is thus constitutively active. The unaltered ABL1 protein plays a central role in numerous processes, including cellular survival, proliferation, migration, and stress response. Therefore, loss of its regulation leads to enhanced and persistent signaling through the PI3K/AKT/mTOR, RAS/RAF/MEK/ERK, and JAK2/STAT pathways [JAK2, CALR, and MPL genes lead to transformed tyrosine kinase activity and enhancement of similar signaling pathways. The most common mutation, JAK2V617F, results in loss of the JAK2 inhibitory domain, allowing for persistent downstream activation. The MPL product is the thrombopoietin receptor, which normally activates the JAK2 pathway when bound by thrombopoietin. Mutations in MPL also result in loss of auto-inhibition and thus autoactivation of the JAK2/STAT signaling pathways [CALR were more recently discovered and are thought to exert oncogenic effects through its altered C terminus. The altered CALR can subsequently bind with MPL intracellularly before being trafficked to the cell surface where it can constitutively activate the thrombopoietin receptor without ligand binding [The most common genetic alterations described above, including pathways ,353. Likpathways . On the  binding .Numerous biological derangements are associated with the previously described mutations commonly detected in MPNs. The subsequent metabolic alterations are closely linked to mitochondrial biogenesis and include modifications in apoptosis, glycolysis, fatty acid metabolism, glutaminolysis, and subsequently in OXPHOS ,357,358.CALR mutations are managed similarly to most other MPNs. However, the trafficking of mutant CALR to the cell surface provides a viable potential treatment modality with either mutant CALR-binding antibody or CALR targeting by T-cell therapy [The treatment of many MPNs is often based on cytoreductive therapy (hydroxyurea) and the prevention of secondary complications (thrombosis) with low-dose aspirin or phlebotomy for PV. Bone marrow transplantation is also available to some patients with MPN, such as high-risk PMF. However, Janus kinase inhibitors, such as ruxolitinib and fedratinib, are also available to patients who fail or cannot tolerate initial therapy. Although rather efficacious in treatment, Janus kinase inhibitors often do not entirely eliminate abnormal myeloid progenitors, contributing to disease relapse. Therefore, these medications are marred by potential full relapse when discontinued. Current investigations have shown that deubiquitinase (DUB) inhibitors (WP1130 and G9) are potentially helpful treatment modalities to induce apoptosis in JAK2V617F mutants. DUB inhibitors can exert their effect by preventing the deubiquitination of JAK2 so that altered JAK2 molecules are passed through the ubiquitin/proteasome pathway. Additionally, DUBs are important in maintaining mitochondrial quality control, and thus their inhibition leads to amplified ROS production Moreover, DUB inhibitor WP1130 induces the activity of Bak and, to a lesser degree, Bax. Consequently, the induction of ROS and Bak/Bax leads to activation of the mitochondrial-dependent apoptotic pathway . Patient therapy . Metabol therapy .FOXO), procaspase 9, and Yes-associated protein (YAP). Similarly, Ras pathway activation induces the PI3K/AKT pathway. Activation of the JAK/STAT pathway promotes cell survival by regulating Bcl-XL and Bcl-2, critical anti-apoptotic proteins [HIF1, HIF2), STAT5, and the glucose transporter genes SLC2A1 and SLC2A3, independent of the environmental oxygen levels. STAT5 and HIF2 are important regulators of glucose uptake and utilization via the SLC2A1/3 transporters. Along the same lines, hexokinase expression is elevated, corresponding with high pyruvate levels for the TCA cycle. Furthermore, HIF1 enhances pyruvate dehydrogenase kinase (PDK2/4) so that the elevation in pyruvate can be quickly used in the TCA cycle. In addition, multiple amino acid levels were elevated compared to normal to provide additional substrates to the TCA cycle. This was partially completed through the use of the SLC1A5 glutamine transporter. Metabolism of glutamine can produce glutamate, which can further be processed into α-ketoglutarate and directly shunted into the TCA cycle within mitochondria. Glutamine appears to be an important factor for intensified OXPHOS, as treatment of BCR/ABL positive CML cell lines with a glutaminase inhibitor drastically hampered OXPHOS [Fusion of BCR/ABL1 results in similar features to those described with JAK2, and it is thought to be due to rampant cellular signaling through multiple pathways due to the kinase activity. BCR-ABL is a vital anti-apoptotic factor by activation of multiple pathways, including Ras, PI3K/AKT, and JAK/STAT pathway, in addition to Myc expression. The PI3K/AKT pathway leads to the inactivation of pro-apoptotic factors by phosphorylation, including Bcl-2 associated death promoter (Bad), forkhead box O transcription factors , such as imatinib. Subsequent second and third-generation TKIs have also been produced in an attempt to overcome TKI resistance. However, despite their effectiveness, some CML patients develop resistance to them, possibly by altered apoptotic pathways, such as by upregulated anti-apoptotic, and pro-survival molecules, such as SRC kinases, FOXO1, XPO1, and STAT3, or by mitochondrial protein changes [Due to the underlying pathogenesis of  changes ,357. TheLymphomas are a diverse group of lymphoid malignancies with heterogeneous molecular, chromosomal, and epigenetic changes. Lymphomas are typically divided into Hodgkin (HL) (10%) and non-Hodgkin lymphomas (90%), with the latter being either B-cell (90%), T-cell or natural killer cell (NK cell) (10%) types .In classical HL (cHL) (95%), there is only a small percentage of neoplastic Reed-Sternberg (RS) and Hodgkin cells intermixed with inflammatory cells. On the other hand, in the nodular lymphocyte-predominant Hodgkin lymphoma (NLP-HL) (5%), the neoplastic cells are different and are designated as lymphocyte-predominant cells, a.k.a. “popcorn” cells. The mainstream treatment of HL is typically with ABVD  and irradiation, where the chemotherapy has been described to primarily increase oxidative stress ,363,364.STAT3, STAT5B, JAK1, JAK2, and PTN1 [TP53 point mutations/deletions, and about 60% had gains of MDM2, latter being a negative regulator of p53 [BCL6 gene was detected in 48% of NLP-HLs [Genetic analysis in cHL is challenging due to the presence of less than 5% tumor cells in the tissue. A recent study, however, analyzed the tumor cells after microdissection, and found that a large proportion (87%) of the cells harbored mutations in the JAK-STAT signaling pathway, including genes and PTN1 . Furtherr of p53 . In addi NLP-HLs ,370.MYC gene). T-cell and NK/T-cell lymphomas are rare, making up about 10–15% of nHLs. Molecular and chromosomal studies are rarely used in addition to immunophenotyping and T-cell receptor rearrangement studies, with the only exception being the frequently recurring chromosomal translocation t, characteristic of ALK-positive anaplastic large-cell lymphomas, where the ALK-negative form has an inferior outcome. In peripheral T-cell lymphomas, alterations in p53, bcl-2, bcl-xl, CD26, EBV, CCND2, CCR4, PRDM1, and TCR gamma are associated with unfavorable prognosis [The by itself also heterogeneous group of B-cell nHLs includes several subtypes, where the tumor cells have a gene-expression profile reflecting their equivalent healthy cells of origin. In addition, they show recurrent genetic, epigenetic, and other molecular changes . Typicalrognosis . Cytotoxrognosis .B-cell nHLs and genetic abnormalities. In DLBCLs, the activated B-cell subtype (ABC) displays worse outcome compared to the germinal center B-cell subtype (GCB). Patients in the ABC type frequently carry mutations in the B-cell receptor (BCR) and the NF-kB pathway genes, such as MYD88, CD79A/B, CARD11, and TNFAIP3, and display active BCR signaling. In addition, MYD88 mutations lead to constitutive activation of the JAK-STAT signaling pathway in these patients. On the other hand, BCL2, MYC, EZH2, and PTEN alterations are more commonly seen in patients with GCB type. Treatment sensitivity, however, are heterogenous in both groups, where MYC, BCL2, and TP53 alterations have been related to therapy resistance. In addition, TP53 mutations carry poor prognosis, especially when co-existing with altered MYD88 [BCL2, genes involved in the JAK-STAT and NF-κB signaling pathways in addition to MYC dysregulations are common. Alterations in BCL2, TP53, EZH2, CREBBP, KMT2D, and MEF2B are more often seen in patients with FL transformation to DLBLC or Burkitt lymphoma [MYC deregulations, such as translocations and mutations, is highly characteristic. Besides others, TP53, MDM4, CCND3, and TCF3 mutations have also been reported in Burkitt lymphoma [CCND1 expression. Additionally, dysregulation in TP53, MEF2B, NOTCH2, WHSC1, and BIRC3. The mTOR pathway is often activated in MCL, which is related to therapy resistance. In addition, TP53 mutations are related to poor prognosis and therapy resistant in MCL [BCL2, or BCL6 alterations) and “triple-hit”  lymphomas are also aggressive in nature, and are part of the high-grade B-cell lymphomas. Double-hit FLs, however, seem to have an indolent clinical behavior [ed MYD88 ,374,375.lymphoma ,379,380.lymphoma . MCLs cht in MCL ,380,381.behavior ,383.nHL treatment. nHL treatment is diverse and includes therapies from R-CHOP , through bone marrow transplantation, to gene transfer therapy, using chimeric antigen receptor-modified T-cell (CAR-T) therapies, and more. We will not discuss these in details, but excellent reviews, such as those from Nebrinsky and co-workers, Chung et al., Klener and Klanova, or Othman and co-workers are suggested in this topic for those interested [terested ,384,385.terested ,387.nHLs and mitochondria. Several genes involved in the development of nHL have been or will be discussed separately with their effect on mitochondrial metabolism and dynamics. Generally: In vitro studies showed that inhibiting glycolysis in lymphoma cells can induce apoptosis and may overcome multidrug resistance [MYC mutations for example are sensitive to glutaminase inhibition [sistance . In DLBCsistance . In addihibition . The hethibition . Intereshibition , higher hibition .NOTCH1 mutations. In addition, Richter transformation is noted to be more common in patients with trisomy 12. Similarly, loss of TP53 with deletion of the short arm of chromosome 17, and TP53 mutations exhibit a poorer prognosis, and resistance to chemotherapy in CLL. Further mutations, such as SF3B1, KRAS, NRAS, BRAF, MYD88, EGR2, MAP2K1, ATM, NOTCH1, POT1, CHD2, XPO1, BIRC3, MED12, FBXW7, ASXL1, NFKBIE, TRAF3, RPS15, and DDX3X are also seen in CLL patients. SF3B1 carries a good prognosis [CLL is the most frequent type of leukemia in adults, characterized by the clonal expansion of predominantly mature B-lymphocytes. It has a generally good prognosis. A frequent genetic lesion, the 13q14 deletion is seen in 50–60% of patients and has a favorable prognosis. Interestingly, unlike in other types of mature B-cell malignancies, translocations involving the immunoglubulin heavy chain is rare. Deletion of 11q22-q23 (del11q), involving the tumor suppressor gene ataxia telangiectasia (ATM) is associated with poor prognosis. The frequent trisomy 12 carries an immediate risk by itself, but has a poor prognosis when co-existent with rognosis ,394,395.TP53 deletion or deficiency enhances glycolysis and increases mitochondrial mass, latter likely by enhanced PGC-1α expression in CLL cells. Both TP53 deficiency and 17p deletion subsequently leads to altered metabolism, impaired autophagy and subsequent Ibratinib-resistance [CLL and mitochondrial changes. Increased mitochondrial mass with accelerated OXPHOS, and increased ROS generation are characteristic of CLL cells. Similarly, sistance ,397,398.sistance .BCR-ABL1 fusion gene, KMT2A (MLL) rearrangements, or hypodiploidity (<44 chromosomes). The genetic mutations are diverse in B-ALL and include: (1) Transcriptional factors promoting early lymphoid cell development, such as PAX5, IKZF1, EBF1, ETV6, ERG, GATA3, and LMO2. (2) Tumor suppressor genes and cell cycle regulators, such as TP53, RB1, and CDKN2A/CDKN2B, BAK1. (3) Cytokine receptors, such as CRLF2, RPOR (4) Kinases, such as ABL1, ABL2, CSF1R, JAK2, PDGFRB. (5) Ras signaling pathway genes, such as KRAS, NF1, NRAS, PTPN11. (6) Lymphoid signaling genes, such as BTLA, and CD200, and (7) Epigenetic modifiers, such as EZH2, CREBBP, SETD2, MLL2, and NSD2. Amongst others, alterations in IKZF1, TP53-, CDKN2A, CREBBP, NR3C2, MSH6, PRPS1, PRPS2, NT5C2 are ETV6 are associated with unfavorable outcome and/or therapy resistance in B-ALL [The vast majority of ALLs are B lymphoblastic leukemias (B-ALLs), mostly occurring in children and adolescents. Inferior clinical outcome has been described in relation to the presence of in B-ALL ,402,403.in B-ALL .MYC, MYCN, and MYCL. The MYC gene codes the c-Myc protein, a transcription factor involved in cell growth, differentiation, metabolism, and cell death regulation [PLOG, PLOG2, and NRF1 expression [The MYC family includes three proto-oncogenes: gulation ,406. c-Mgulation ,407. Simgulation ,345,408.gulation ,411,412.gulation  and glutgulation . Myc alsgulation , and incpression . The exppression .MYC mutations or alterations resulting in overexpression.Aberrant expression of c-Myc has been described in various hematologic malignancies, including Burkitt lymphoma, “double-hit/ “triple-hit” DLBCLs, high-grade B-cell lymphomas, multiple myeloma (MM), some mantle cell lymphomas, and AMLs. Increased c-Myc expressions alone or with additional Bcl-2 or Bcl-6 alterations correlate with poor clinical outcome, or therapy resistance ,416,417.MYC, CCND1/CCND2/CCND3 (Cyclin D), FGFR3 (fibroblast growth factor receptor 3), MMSET (histone methyltransferase multiple myeloma SET domain), KRAS, NRAS, BRAF, TP53, and MAF/MAFA/MAFB (musculoaponeurotic fibrosarcoma) [MAF translocations  and deletion of 17p (TP53), although relatively less common, portrays a poor prognosis [MM is a neoplastic disorder of plasma cells, which are terminally differentiated B-cells. Numerous genetic alterations, including mutations and epigenetic changes, have been described in the dysregulation of plasma cells that lead to dyscrasias. Some significant genetic changes include sarcoma) ,329,419.As previously mentioned, since the initial discovery of necroptosis in the early 2000s, it has been increasingly investigated as a potential source of treatment for many conditions, including variety of neoplastic processes ,421. PriChanges in cellular metabolism in MM are numerous, including a radical increase in glycolysis and OXPHOS. Enhanced glycolysis leads to higher pyruvate levels within the cell, which can be turned into lactate or acetyl-CoA as a substrate for the TCA cycle to go through OXPHOS. Acetyl-CoA can also be used for fatty acid synthesis. These processes are essential for neoplastic plasma cells in MM to proliferate and produce immunoglobulins in a stringent environment such as the bone marrow. The boosting of metabolic substrates and their subsequent processes within MM cells occur through numerous genetic changes that connect to the previously discovered changes occurring in MM discussed previously.MYC, MAF, MMSET, FGFR3, and CCND1 lead to distinctly altered cellular metabolism through influence on enzymes, metabolic substrates, and various cellular transporters. The changes induced by these alterations enable enhanced cell survival and proliferation in MM. One of the main effectors in altered cellular metabolism is the protein kinase B cascade (AKT). This pathway plays a central role in multiple myeloma through metabolic orchestration leading to upregulation of glycolysis, glutaminolysis, pentose phosphate shunting, lipid synthesis, and nucleotide production while also decreasing fatty acid oxidation [AKT is an essential inhibitor of FOXO, which is necessary for p53-dependent cell death. AKT is activated by cyclin D1, MYC, and FGFR3, while AKT further upregulates MMSET, which plays a pivotal role in opening chromatin for enhanced activity by demethylation. MMSET is also crucial for glycolytic processing and subsequent shunting through the pentose phosphate pathway (PPP). Interestingly, MMSET appears to be of particular importance in multiple myeloma cells containing the t alteration. Cyclin D1 and MYC are stabilized by the activity of KRAS and ERK, while the activity of ubiquitin-specific peptidase 5 (USP5) helps prevent MAF degradation in t, t, t, and t cells. Cancer lines with high levels of MAF are known to be resistant to proteasome inhibitors, such as bortezomib, through increased proteasomal activity. In addition, MYC appears to enhance both glycolysis and glutaminolysis in MM by acting on glutamine, lactate, and glucose transporters for augmented uptake from the environment [Genetic alterations in xidation . Furtherironment .MFN1 is associated with inferior survival in MM [TFAM, PGC1A, POLG2, and TWNK have also been linked to poor prognosis in MM [Interestingly, MM cell lines have demonstrated increased fusion, which is thought to be regulated by Myc . In addial in MM . On the is in MM .Interestingly, MM cells are able to internalize mitochondria, transferred from the neighboring nonmalignant bone marrow stromal cells, which seems to be at least in part CD38-driven .MAF, are basic region leucine zipper (bZIP)-type transcription factors. Large MAFs (lMAFs), such as MAFA, MAFB, c-MAF and NRL are pro-oncogenes, and bind to DNA sequences called MAF recognition elements (MAREs), where they modulate expression of several genes, such as CCDN2, FOS, JUN, CREB, MTORC2 and ATF [sMAF), such as MAFF, MAFG and MAFK bind to the same region via competitive binding, inhibiting transcription. The ratio of lMAFs and sMAFs are therefore important determinants of transcription activation. In addition, posttranslational modifications also alter the activity of the MAF proteins [Musculoaponeurotic fibrosarcoma (MAF) proteins, encoded by  and ATF ,424,425.proteins .MAF has multiple roles in cellular metabolism in MM, including elevated insulin secretion for enhanced MM cell glucose uptake, activating ARK5, which has been linked to increased OXPHOS, and glutamine metabolism. Glycolysis and glutaminolysis are of particular importance in MM due to the need for antibody production. The ARK5/CDK4 inhibitor ON123300 has been shown to induce apoptosis in MM cell lines. MAF translocations, however, were not predictive of ARK5/CDK4 treatment in this study ,426.c-MAF was found to be overexpressed, whereas in MM, aberrant c-MAF, MAFA, and MAFB gene expressions have been described. As mentioned previously, MAF mutation is associated with a poor prognosis in MM [In about 60% of angioimmunoblastic T-cell lymphomas, is in MM ,425,427.Here we aim to summarize potential therapies targeting mitochondria, some of which we already have addressed in previous chapters. In addition, specific therapies for malignancies with certain genetic mutations can be found in the chapters where those genes are discussed in detail.Cellular metabolism can be inhibited via various enzymes in different metabolic pathways, which are promising therapeutic targets in cancer therapy. These include drugs targeting ETC, TCA, glycolysis, and fatty acid oxidation and synthesis enzymes. Some of these enzymes are localized in the mitochondria, whereas others are found in the cytosol  7,428,4,437,438.Inhibition of mtDNA translation and transcription ,29,30,31Interfering with mitochondrial dynamics, including mitochondrial fission/fusion ,443, mitThere is substantial evidence that genetic alterations in hematologic malignancies are in close relationship with mitochondrial metabolism, dynamics, cell death pathways, and mtDNA transcription and translation. Targeting these pathways are promising future therapies, especially in therapy-resistant cases.


The molecular pathogenesis of sebaceous carcinoma is largely unknown so far. The main aim of our study was to investigate genetic alterations in ocular and extraocular sebaceous carcinoma in Korean patients. By applying targeted next-generation sequencing, we demonstrated a distinct mutational profile in ocular and extraocular sebaceous carcinoma. In addition, clinically actionable variants involving tyrosine kinase genes and homologous recombination deficiency-associated genes were detected, suggesting the possibility of targeted therapeutic trials in intractable sebaceous carcinoma cases.TP53 and PIK3CA genes were frequently mutated in both SeC-Os and SeC-EOs with slight predominance in SeC-Os, whereas the NOTCH1 gene was more commonly mutated in SeC-EOs. In clinical correlation, mutations in RUNX1 and ATM were associated with development of distant metastases, and alterations in MSH6 and BRCA1 were associated with inferior progression-free survival . In conclusion, our study revealed distinct genetic alterations between SeC-Os and SeC-EOs and some important prognostic molecular markers. Mutations in potentially actionable genes, including EGFR, ERBB2, and mismatch repair genes, were noted, suggesting consideration of a clinical trial in intractable cases.The biological behavior of sebaceous carcinoma (SeC) is relatively indolent; however, local invasion or distant metastasis is sometimes reported. Nevertheless, a lack of understanding of the genetic background of SeC makes it difficult to apply effective systemic therapy. This study was designed to investigate major genetic alterations in SeCs in Korean patients. A total of 29 samples, including 20 ocular SeCs (SeC-Os) and 9 extraocular SeCs (SeC-EOs), were examined. Targeted next-generation sequencing tests including 171 cancer-related genes were performed.  Sebaceous carcinoma (SeC) is a rare but aggressive neoplasm that is relatively prevalent in the Asian population ,2,3. TheTP53, NOTCH1 and NOTCH2 . Th. Th24]. http://www.r-progect.org/, accessed on 10 September 2021) to generate an oncoplot, which depicts the top 20 mutated genes in SeCs. We expanded the altered genes of each SeC by weighting frequent recurrent mutations on String with adjustment of settings , no more than 5 interactors). Then, we evaluated protein–protein interaction (PPI) and conducted gene ontology (GO) pathway analysis using String v. 11.0 [We used the maftools  package  v. 11.0 .p-values were two-sided, and a p-value of less than 0.05 was considered statistically significant.Clinicopathologic variables were correlated with the presence or the frequency of genomic alterations in SeC-Os and SeC-EOs. The differences were analyzed by using Pearson’s chi-square test, Fisher’s exact test, or the Mann–Whitney U test. Progression-free survival (PFS) of SeC patients was analyzed by Kaplan–Meier survival curves. All the statistical analyses were performed using the SPSS (v22.0) software package . All The clinical profile of all patients is summarized in the p = 0.864).Targeted sequencing in 29 SeCs revealed 129 pathogenic mutations in 34 different genes . On averTP53, which harbored a total of 29 mutations in 13 cases (65.0%). Among 29 mutations, 21 were missense mutations, and 7 were nonsense mutations. The remaining 1 alteration occurred in the spliced acceptor site (c.920-1G > A). A total of 6 mutations in PIK3CA were observed in 4 cases (20.0%). SMARCA4, ATM, FBXW7, and RB1 were mutated in 3 cases (15.0%). In SeC-EOs, the most commonly mutated gene was NOTCH1, of which a total of 6 alterations were detected in 5 tumors (55.5%). There were 6 missense mutations, 3 nonsense mutations, and 1 frameshift mutation. In 3 (33.3%) tumors, a total of 8 TP53 alterations were observed, of which 7 were missense mutations, and the remaining 1 was a frameshift mutation. For BRCA1, MSH2, and SMARCA4, a total of 2 cases (22.2%) showed pathogenic variants, respectively . Although TP53 was more frequently mutated in SeC-Os than in SeC-EOs, and RB1 was mutated only in SeC-O cases, the difference was not statistically significant (p = 0.532). Likewise, the mutations in MSH2 were only observed in SeC-EOs, but the difference was not significant (p = 0.234).Compared with SeC-Os, mutations in RUNX1 were observed in 2 SeC-Os, and mutations in ATM were identified in 3 SeC-Os and 1 SeC-EO. Although the frequency of mutations in these 2 genes were low, they were associated with the development of distant metastases during the follow-up period . However, cases harboring mutations in RUNX1 and ATM were not associated with shorter PFS in Kaplan–Meier analysis (both p > 0.05) , whereas in SeC-EOs, cases with BRCA1 mutations presented inferior PFS (p = 0.046) (Mutations in  > 0.05) . In SeC-= 0.046) .PIK3CA) and Notch signaling pathway (NOTCH1) were considered other tumorigenic pathways in SeC-O and Sec-EO, respectively  pathway, and MMR pathway were mainly responsible for the pathogenesis of both SeC-O and SeC-EO . Additioectively . In GO aectively . In SeC-ectively .TP53 was the most frequently mutated gene across the 5 subtypes. FBXW7 mutations were significantly enriched in the luminal 1 subtype compared with the other subtypes (p = 0.006). Likewise, mutations in NOTCH1 were observed only in the core basal subtype (p = 0.003). Although mutations in TP53 and SMARCA4 were more common in the luminal 1 subtype, the differences were not significant (p > 0.05). Mutations involving ERBB2 were detected only in the luminal 1 subtype.The molecular subtypes were determined in a total of 22 cases with available tissue for IHC and FISH analysis. In SeC-Os, 6 (42.9%), 2 (14.3%), 2 (14.3%), 4(28.6%), and 0 (0.0%) cases were classified as luminal 1, luminal 2, HER2, all-negative, and core basal type . In SeC-MLH1 (p.M587Hfs*6) with a variant allele frequency (VAF) of 45.5% in SeC-O and 60.16% in SeC-EO  was included in this study. This patient had a microsatellite instability (MSI)-high colon cancer, followed by early gastric carcinoma and SeC-O 2 years later, and then was diagnosed with metachronous SeC-EOs. The NGS study performed in 2 SeCs revealed a common mutation of n SeC-EO . Considemutation .MLH1, MSH2, and MSH6 was 1, 1, and 2, respectively. Mutations in both MSH2 and MSH6 were detected in the remaining 1 patient. Only 1 case revealed a possible germline variant in MSH6 (p.F1088Lfs*5) with a VAF of 47.66% but no other accompanying internal malignancies conforming to MTS. Except for that case, the VAFs of the other mutations were not suggestive of germline mutations. Alterations in MMR genes were associated with mutations involving KMT2A (p = 0.010) and NF1 (p = 0.052) with borderline significance. The number of pathogenic mutations was higher in tumors with MMR gene alterations than in others with borderline significance (p = 0.053).In addition to the patient described above, 5 other patients had alterations in MMR genes . The numPIK3CA and TP53. Likewise, in sample 7 and its recurrent lesion (sample 15), the same BRCA1 nonsense mutation was detected (TP53 p.Q192* and BRCA1 p.R1443* mutations increased in the recurrent lesions (FLT4 (p.E1336K), which is a variant of undetermined significance.There were 3 cases in which the mutation profile of the primary site and recurrent or metastatic tumors could be compared . Among tdetected . Notably lesions . On the TP53, NOTCH1, PIK3CA, and SMARCA4, whereas SeC-Os revealed mutations in TP53, PIK3CA, FBXW7, and RB1. Notably, NOTCH1 mutations were exclusively found in SeC-EOs. Given that most of these NOTCH1 mutations are related to a loss of function, NOTCH1 may play a role as tumor suppressor in SeC-EOs. On the other hand, FBXW7, which is known to negatively regulate NOTCH [PIK3CA [FBXW7 [PTEN, and TSC1 [In the current study, we comparatively analyzed the mutational profile of SeC-Os and Sec-EOs using targeted NGS. Our results suggest that SeC-Os and SeC-EOs are related but distinct entities with different molecular pathogeneses. SeC showed frequent alterations involving te NOTCH  and lead [PIK3CA , FBXW7 [A [FBXW7 , PTEN, aand TSC1 , were moTP53, NOTCH1, NOTCH2, ZNF750, and RREB1 are specific to SeCs, whereas truncation mutations in NOTCH1 are concentrated in SeC-EOs [ZNF750, while SeC-EOs showed a high mutation burden associated with MSI and UV damage [ZNF750 is known as a transcription factor involved in keratinocyte differentiation [ZNF750 was not included in our gene panel, and there are other studies that have published some controversial results [ZNF750, the mutational profile of SeCs in our cohort was similar to that of cutaneous squamous cell carcinoma (SqCC), in which TP53 and NOCTH1/2 are characteristically mutated [PTCH1, SMO, or SUFU, were the mainly altered genes in BCC in addition to TP53, unlike SeCs [Our results are in line with the previous studies, which have also demonstrated frequent activation mutations in the PI3K/AKT/mTOR pathway in SeCs ,21,22. T SeC-EOs . NotablyV damage . Since Zntiation ,46, thei mutated ,48. Basaike SeCs . These rFBXW7 mutations were significantly enriched in the luminal 1 subtype, and mutations in NOTCH1 were observed only in the core basal subtype (p = 0.003). Although SeCs and breast cancer are similar in that PIK3CA and TP53 are the most common mutations, there was little overlap between the two tumors in terms of the types of alterations according to each molecular subtype [BRCA1, CCNE1, AKT3, or MYC [NOTCH1 mutations were relatively common in our SeC-EOs. Wang et al. demonstrated that approximately 13% of triple-negative breast cancer cases carry NOTCH1 mutations, which are centered in the PEST domain, and ultimately lead to the activation of the Notch signaling pathway [NOTCH1 mutations were predicted to damage protein function. Although SeCs can be classified into five immunohistochemical subtypes, their mutational profile did not completely match with these subtypes adopted from breast cancer.Our group previously proposed five molecular subtypes of SeCs according to the HRs, HER2, and CK5/6, in a similar way to breast cancer: luminal 1, luminal 2, HER2, all-negative, and core basal subtypes . While S subtype ,51. For , or MYC ,51; howe pathway . In contMLH1 mutations in both SeC-O and SeC-EO. Interestingly, SeC-EO did not share other pathogenic mutations with SeC-O, suggesting multiple individual primary tumors rather than metastasis. In the other five patients with MMR defects, MLH1, MSH2, and MSH6 mutations were observed mostly in low VAF, suggesting a somatic origin. Since various types of mutations were found in these cases in addition to MMR defects, it is difficult to determine which of them is the driving mutation. Although we could not confirm the MSI status of these tumors due to tissue unavailability, it is possible that DNA instability induced by MMR defects resulted in numerous mutations. Therefore, we suggest that SeC should also be screened for MSI as for colorectal carcinoma and endometrial carcinoma. Previous studies have also demonstrated that somatic alterations in MMR genes occur especially in SeC-EOs, which show an MSI-high phenotype [Mutations in MMR genes were found in a total of six patients, including one with classical MTS harboring pathogenic henotype ,21.TP53 p.Q192* in sample 4 and BRCA1 p.R1443* in sample 7) or decreased (TP53 p.R342P in sample 4) in recurrent lesions, suggesting an expansion of a specific tumoral subclone that conveys a survival advantage. Notably, samples 6 and 10 did not share any pathogenic variants. Instead, a variant of undetermined significance (FLT4 p.E1336K) was detected in both lesions. FLT4, also known as VEGFR3, is an oncogene that mediates cell proliferation, survival, and invasion [FLT4 in solid malignancies are not commonly reported, mutations in colorectal cancer [FLT4 p.E1336K has not previously been reported; however, the possibility of an oncogenic role can be considered under the above circumstances.We had three pairs of primary and matched recurrent or metastatic lesions. In two patients, some of the pathogenic variants of the primary lesions remained in the recurrent lesions. The VAFs of certain variants in the primary lesions were significantly increased (l cancer  and non-l cancer  have beePIK3CA mutations account for 20% (4/20) of SeC-Os, and it can be targeted by PI3K inhibitors similar to hormone receptor-positive breast cancer [BRCA1, BRCA2, ATM, and KMT2A, were detected in both SeC-Os and SeC-EOs, suggesting a possible role of poly (ADP-ribose) polymerase inhibitors [ERBB2 (p.A775_G776insYVMA), for which a response to pan-HER kinase inhibitors has been reported in various types of cancer [EGFR (exon 19 deletion) and BRAF (p.N581S), were detected, which can also provide grounds for potential targeted therapy [NOTCH1 mutations were prominent in SeC-EOs, most alterations were associated with a loss of protein function; therefore, NOTCH1 inhibitors do not seem promising based on our findings.This study identified some potentially targetable alterations in SeCs. First, t cancer . Notablyhibitors ,58. Secof cancer . In addi therapy ,61. Fina therapy ,63. AlthRUNX1  and ATM  were associated with the development of distant metastasis during the follow-up period. However, cases with mutations in RUNX1 or ATM were not associated with shorter PFS. This might be due to the fact that local recurrences also contribute to disease progression, especially in SeC-Os. RUNX1 is frequently altered in hematopoietic malignancies [RUNX1 are also found in solid malignancies, such as breast cancer [RUNX1 knockdown induces the activation of transforming growth factor β and WNT signaling pathways, thereby promoting the epithelial–mesenchymal transition (EMT) process [ATM have been reported in various solid tumors, including endometrial cancer, bladder cancer, and colorectal cancer [ATM protein expression was associated with poor overall survival in breast cancer [ATM mutation are generally unknown to date. ATM signaling is known to induce tumor progression in a nuclear factor kappa B-dependent manner that promotes EMT [vbeta3 integrin pathway, which can trigger invasive and metastatic potential [RUNX1 and ATM might contribute to developing metastasis. Our findings suggest that mutations in RUNX1 and ATM can serve as prognostic markers in SeCs. In addition, MSH6 and BRCA1 mutations were associated with inferior PFS in SeC-Os and SeC-EOs, respectively. For MMR gene defects and BRCA mutations, contradictory results have been reported [MSH6 and BRCA1 mutations in SeC.One of the novel findings of the present study was that mutations in gnancies ,65. Albet cancer ,67,68,69 process ,71. Mutal cancer ,67. Losst cancer , cervicat cancer , and colt cancer , althougotes EMT . Moreoveotential . As the otential , mutatioreported ,79,80,81PIK3CA, HRD-related genes, and MMR genes, which could lead to clinical benefit in patients with advanced SeCs.This is the first study performing NGS in Korean SeC-O and SeC-EO patients. Sequencing revealed a distinct pattern of genetic alterations in SeC-Os and SeC-EOs. Additionally, various potentially targetable alterations were detected, including


The complement system represents a crucial part of innate immunity. It contains a diverse range of soluble activators, membrane-bound receptors, and regulators. Its principal function is to eliminate pathogens via activation of three distinct pathways: classical, alternative, and lectin. In the case of viruses, the complement activation results in effector functions such as virion opsonisation by complement components, phagocytosis induction, virolysis by the membrane attack complex, and promotion of immune responses through anaphylatoxins and chemotactic factors. Recent studies have shown that the addition of individual complement components can neutralise viruses without requiring the activation of the complement cascade. While the complement-mediated effector functions can neutralise a diverse range of viruses, numerous viruses have evolved mechanisms to subvert complement recognition/activation by encoding several proteins that inhibit the complement system, contributing to viral survival and pathogenesis. This review focuses on these complement-dependent and -independent interactions of complement components  with several viruses and their consequences. The innate immune system is characterised by its ability to distinguish between “self” and “non-Self”. The complement system plays a crucial part in the innate immune surveillance against viruses through several mechanisms that prevent host viral infection. It can be activated through three pathways: the classical, the alternative, and the lectin, depending upon the recognition subcomponents and the ligand that trigger its activation. The classical pathway is activated  by eitheThe lectin pathway is a homologue of the classical pathway. It is triggered by the binding of mannan-binding lectin (MBL) and ficolins to carbohydrate patterns on the pathogen surface or carbohydrate structures on antibodies, including the common IgG glycosylation variant IgG-G0 and polymeric IgA ,5,6,7,8.2O) . C3i binds with factor B, a serine protease, forming a complex, called C3iB. C3iB enables factor D to cleave factor B to Bb, forming C3iBb. This newly formed C3iBb cleaves C3 to form C3b and C3a. The C3b formed binds to the pathogen surface where they further bind more factor B, which are then cleaved by factor D to form C3bBb, similar to the C3 convertase of the other two pathways.A distinct mechanism  activateThe three complement pathways converge on C3 convertase, which is considered the complement system’s central component . The C3 The C3a and C5a generated during complement activation are anaphylatoxins. C5a is known to bind to cells expressing C5aR and C5L2, while C3a is known to bind to cells expressing C3aR ,13,14. BDysregulated activation of the classical and lectin pathways during ischemia-reperfusion injury is known to cause necrosis, apoptosis, and possibly autophagy of the tissue, thus potentially causing permanent tissue or organ damage . Common This review focuses on the complement activation-dependent and independent functions of complement components  as soluble pattern recognition receptors for several viruses .The complement system employs multiple mechanisms that inhibit the viral infection of the host. Complement activation neutralises viruses via (a) viral opsonisation by complement components; (b) virolysis, which occurs when the MAC produces holes on the viral membrane; and (c) the production of anaphylatoxin ,41,42. TThe complement system’s importance against pathogens is best exhibited by the coevolution of the pathogens with the hosts. Viruses mainly achieve complement evasion  by eitheGamma herpesviruses such as Murine gamma-herpesvirus 68 (γ-HV68), Herpesvirus saimiri (HVS), and Kaposi’s sarcoma-associated herpesvirus (KSHV) are known to encode homologues of regulator of complement activation (RCA). The complement control protein homologue (CCPH) produced by the HVS shares a similar global structural layout with DAF and MCP. CCPH is known to inhibit complement activation by accelerating decay of the C3 convertase and by its FI cofactor activity for the cleavage of C4b and C3b, thus inhibiting all three complement pathways ,51. In aThe coat protein of astrovirus (CoPt) inhibits the activation of the classical and lectin pathways by binding C1q and MBL ,66. CoPtAnother complement evasion mechanism used by viruses  involvesFlaviviruses, which cause diseases such as Dengue (DENV), Zika, and Yellow fever (YFV), produce a non-structural protein 1 (NS1), which is a secreted non-structural glycoprotein that accumulates in the blood and is displayed on the surface of infected cells. The West Nile Virus (WNV) NS1 has been shown to bind factor H, which retains its co-factor activity . SimultaHuman C1q can recognise and bind a variety of self and non-self ligands and regulate a range of homeostatic functions such as clearance of immune complexes, pathogens , and necrotic and apoptotic cells . C1q is The viral neutralizing activity of C1q against Influenza A Virus (IAV) has been studied using in vitro models. C1q was found to enhance haemagglutinin (HA)-specific monoclonal antibody-mediated inhibition of IAV attachment to host cells (>100-fold) at the cell-binding stage . FurtherC1q interaction with retroviruses involves the globular region of C1q and envelope glycoproteins of several viruses, including gp41 and gp120 of HIV-1, p15E of murine leukaemia virus (MuLV), and gp21 of human T lymphotropic virus (HTLV)-1 . C1q viaBa-L or HIV-1IIIB . C. C124]. CFP (Complement factor P) encodes for properdin protein [Neisseria meningitidis infection [The human properdin gene  protein , which c protein ,127,128. protein . Properd protein ,130. Pro protein . It prev protein ,135,136.nfection .Neisseria meningitidis lipopolysaccharide and Chlamydia pneumonia [Neisseria by binding to lipo-oligosaccharide (LOS) [Properdin can exert immune functions in a complement-independent manner, including its ability to bind to microbial targets neumonia . Properdneumonia  via direneumonia ,141. In de (LOS) ,142.de novo KSHV infection [+-T cells, which play a significant role in the elimination and clearance of viral infection [Kaposi’s sarcoma-associated herpesvirus (KSHV) infection induces cell surface expression of properdin in the infected endothelial cells, which is essential for complement activation during nfection . Dengue nfection . Properdnfection . Sites infection . Properdnfection ,148,149.nfection ,150. Addnfection ,135,151.The alternative pathway plays an important role in the protection against viruses. Activation of the alternative pathway is limited on the self-cells by various negative regulators, including FH, the primary soluble regulator. In the presence of sialic acid found on self-cells, the affinity of FH for surface-bound C3b is increased and allows FH to differentiate between self and non-self-cells ,152,153.FH is part of the FH family, a group of highly related multifunctional protein primarily synthesised in the liver, and include FH, the spliced variant FH-like protein 1 (FHL-1) and FH-related proteins (FHR) 1–5 ,158. The10) of M1 of IAV in H1N1 subtype infected A549 cells, while upregulation (2 log10) was seen in H3N2-infected cells. FH was found to trigger anti-inflammatory responses in H1N1 infected A549 cells while provoking pro-inflammatory responses in the case of the H3N2 subtype. mRNA expression levels of TNF-α, IL-12, IL-6, and IFN-α were upregulated, while RANTES was downregulated in H1N1-infected A549 cells treated with FH at 6 h post-infection. In the case of the H3N2 subtype, enhanced mRNA levels of these pro-inflammatory cytokines were observed. The same study also revealed that FH could act as an entry inhibitor for the H1N1 subtype, as evident by a reduction in luciferase reporter activity in MDCK cells transduced with H1N1 pseudotyped lentiviral particles [West Nile virus (WNV) is an enveloped RNA Flavivirus; the RNA is translated in the host cytoplasm as a polyprotein and then cleaved into structural and non-structural (NS) proteins by the virus- and host-encoded proteases ,164. WNVarticles .2+-dependent pattern recognition innate immune molecule, which acts as a potent opsonin against invading pathogens [S. aureus infection [−/− mice show increased susceptibility to IAV infection from highly glycosylated viral strains of IAV compared to wild-type (WT) mice [−/− mice, suggesting that MBL may also have an adverse effect against some strains of IAV infection [Human mannan-binding lectin (MBL) is a soluble, Caathogens . MBL is athogens ,168. Theathogens ,170,171.athogens ,173,174.athogens . Humans athogens , but twoathogens ,177 and athogens . MBL-A anfection . Similarnfection . Howevernfection . Furthernfection . MBL cannfection . MBL cannfection ,181,182.nfection ,183 thronfection ,185. Thenfection ,189,190.nfection . Howevernfection ,191,192.WT) mice . Howevernfection .MBL interacts with HIV-1 via its N-linked glycosylated envelope glycoprotein, gp120 . HIV-1 cNeutralisation of HIV-1 by MBL can be complement-independent, involving opsonisation to enhance phagocytosis by macrophages and dendritic cells (DCs) . InteresMBL also employs viral glycoprotein-mediated complement-dependent or independent mechanisms, as seen in the case of IAV ,193, sevStaphylococcus aureus [Genetic polymorphisms found in the MBL gene are associated with the progression of liver disease as a cause of chronic HBV and HCV infection ,216,217.s aureus  and HSV-s aureus .Higher susceptibility to SARS infection is reported in MBL-deficient individuals. Reduced serum levels of MBL were observed in patients infected with SARS-CoV infection ,207. MBLFicolins are important innate immune PRRs, belonging to a group of oligomeric lectins, composed of N-terminal rich in cysteine residues, a collagen-like domain , and a neck region . Like coN-acetylglucosamine (GlcNAc) or N-acetylgalactosamine ) on microbial pathogens [In humans, three ficolins have been identified: M (ficolin-1), L (ficolin-2), and H-ficolin (ficolin-3) . Only twathogens ,242. Thiathogens ,244. Furathogens ,248,249.Like MBL, all ficolins can trigger the lectin pathway via MASP, induce phagocytosis via opsonisation, and stimulate the secretion of pro-inflammatory cytokines and nitric oxide by macrophages . Human LInteraction between L-ficolin and HCV triggers lysis of HCV infected cells via deposition of C4. However, L-ficolin interaction can be abrogated if the E2 glycoprotein of the HCV is not glycosylated . FurtherThe important role of the complement system during viral infection cannot be overstated. It plays a critical role in determining the outcome of many viral infections. Further research in this area will help elucidate the complex mechanisms involved in the viral-host interaction and help develop improved therapeutics to combat viral infections. Furthermore, understanding the immune suppression mechanisms employed by viruses can help develop therapeutics.The complement-activation independent functions of several complement components against viral entry and cytokine storm appear to suggest the possibility of using recombinant form and fragments of complement inhibitors, as anti-viral therapy.