Integrative methylome-transcriptome analysis unravels cancer cell vulnerabilities in infant MLL-rearranged B cell acute lymphoblastic leukemia.
B cell acute lymphoblastic leukemia (B-ALL) is the most common childhood cancer. As predicted by its prenatal origin, infant B-ALL (iB-ALL) shows an exceptionally silent DNA mutational landscape, suggesting that alternative epigenetic mechanisms may substantially contribute to its leukemogenesis. Here, we have integrated genome-wide DNA methylome and transcriptome data from 69 patients with de novo MLL-rearranged leukemia (MLLr) and non-MLLr iB-ALL leukemia uniformly treated according to the Interfant-99/06 protocol. iB-ALL methylome signatures display a plethora of common and specific alterations associated with chromatin states related to enhancer and transcriptional control in normal hematopoietic cells. DNA methylation, gene expression, and gene coexpression network analyses segregated MLLr away from non-MLLr iB-ALL and identified a coordinated and enriched expression of the AP-1 complex members FOS and JUN and RUNX factors in MLLr iB-ALL, consistent with the significant enrichment of hypomethylated CpGs in these genes. Integrative methylome-transcriptome analysis identified consistent cancer cell vulnerabilities, revealed a robust iB-ALL-specific gene expression-correlating dmCpG signature, and confirmed an epigenetic control of AP-1 and RUNX members in reshaping the molecular network of MLLr iB-ALL. Finally, pharmacological inhibition or functional ablation of AP-1 dramatically impaired MLLr-leukemic growth in vitro and in vivo using MLLr-iB-ALL patient-derived xenografts, providing rationale for new therapeutic avenues in MLLr-iB-ALL.
['Tejedor|Juan Ramón|JR|', 'Bueno|Clara|C|', 'Vinyoles|Meritxell|M|', 'Petazzi|Paolo|P|', 'Agraz-Doblas|Antonio|A|', 'Cobo|Isabel|I|', 'Torres-Ruiz|Raúl|R|', 'Bayón|Gustavo F|GF|', 'Pérez|Raúl F|RF|', 'López-Tamargo|Sara|S|', 'Gutierrez-Agüera|Francisco|F|', 'Santamarina-Ojeda|Pablo|P|', 'Ramírez-Orellana|Manuel|M|', 'Bardini|Michela|M|', 'Cazzaniga|Giovanni|G|', 'Ballerini|Paola|P|', 'Schneider|Pauline|P|', 'Stam|Ronald W|RW|', 'Varela|Ignacio|I|', 'Fraga|Mario F|MF|', 'Fernández|Agustín F|AF|', 'Menéndez|Pablo|P|']
D000818:Animals D049109:Cell Proliferation D050676:Core Binding Factor Alpha 2 Subunit D018899:CpG Islands D019175:DNA Methylation D044127:Epigenesis, Genetic D000081122:Epigenome D020869:Gene Expression Profiling D015973:Gene Expression Regulation, Leukemic D015322:Gene Rearrangement, B-Lymphocyte D011495:Histone-Lysine N-Methyltransferase D006801:Humans D007223:Infant D051379:Mice D016688:Mice, Inbred NOD D051788:Myeloid-Lymphoid Leukemia Protein D015452:Precursor B-Cell Lymphoblastic Leukemia-Lymphoma D018808:Transcription Factor AP-1 D023041:Xenograft Model Antitumor Assays
Leukemias Epigenetics Transcription Genetics Oncology