Six1 regulates leukemia stem cell maintenance in acute myeloid leukemia.
Molecular genetic changes in acute myeloid leukemia (AML) play crucial roles in leukemogenesis, including recurrent chromosome translocations, epigenetic/spliceosome mutations and transcription factor aberrations. Six1, a transcription factor of the Sine oculis homeobox (Six) family, has been shown to transform normal hematopoietic progenitors into leukemia in cooperation with Eya. However, the specific role and the underlying mechanism of Six1 in leukemia maintenance remain unexplored. Here, we showed increased expression of SIX1 in AML patients and murine leukemia stem cells (c-Kit+ cells, LSCs). Importantly, we also observed that a higher level of Six1 in human patients predicts a worse prognosis. Notably, knockdown of Six1 significantly prolonged the survival of MLL-AF9-induced AML mice with reduced peripheral infiltration and tumor burden. AML cells from Six1-knockdown (KD) mice displayed a significantly decreased number and function of LSC, as assessed by the immunophenotype, colony-forming ability and limiting dilution assay. Further analysis revealed the augmented apoptosis of LSC and decreased expression of glycolytic genes in Six1 KD mice. Overall, our data showed that Six1 is essential for the progression of MLL-AF9-induced AML via maintaining the pool of LSC.
['Chu|Yajing|Y|https://orcid.org/0000-0001-6239-1519', 'Chen|Yangpeng|Y|', 'Li|Mengke|M|', 'Shi|Deyang|D|', 'Wang|Bichen|B|', 'Lian|Yu|Y|', 'Cheng|Xuelian|X|', 'Wang|Xiaomin|X|', 'Xu|Mingjiang|M|', 'Cheng|Tao|T|', 'Shi|Jun|J|', 'Yuan|Weiping|W|https://orcid.org/0000-0001-8288-5022']
D000818:Animals D049109:Cell Proliferation D015972:Gene Expression Regulation, Neoplastic D055785:Gene Knockdown Techniques D018398:Homeodomain Proteins D006801:Humans D015470:Leukemia, Myeloid, Acute D051379:Mice D051788:Myeloid-Lymphoid Leukemia Protein D009374:Neoplasms, Experimental D014411:Neoplastic Stem Cells D015514:Oncogene Proteins, Fusion D011379:Prognosis D019009:Proto-Oncogene Proteins c-kit D015854:Up-Regulation
Six1 leukemia stem cell acute myeloid leukemia MLL-rearranged leukemia glycolysis