| Literature DB >> 33860275 |
Seongseok Yun1, Nicole D Vincelette1, Xiaoqing Yu2, Gregory W Watson1, Mario R Fernandez3, Chunying Yang3, Taro Hitosugi4, Chia-Ho Cheng2, Audrey R Freischel3, Ling Zhang5, Weimin Li3, Hsinan Hou6, Franz X Schaub3, Alexis R Vedder1, Ling Cen2, Kathy L McGraw1, Jungwon Moon1, Daniel J Murphy7, Andrea Ballabio8,9,10,11,12, Scott H Kaufmann4, Anders E Berglund2, John L Cleveland13.
Abstract
MYC oncoproteins regulate transcription of genes directing cell proliferation, metabolism and tumorigenesis. A variety of alterations drive MYC expression in acute myeloid leukemia (AML) and enforced MYC expression in hematopoietic progenitors is sufficient to induce AML. Here we report that AML and myeloid progenitor cell growth and survival rely on MYC-directed suppression of Transcription Factor EB (TFEB), a master regulator of the autophagy-lysosome pathway. Notably, although originally identified as an oncogene, TFEB functions as a tumor suppressor in AML, where it provokes AML cell differentiation and death. These responses reflect TFEB control of myeloid epigenetic programs, by inducing expression of isocitrate dehydrogenase-1 (IDH1) and IDH2, resulting in global hydroxylation of 5-methycytosine. Finally, activating the TFEB-IDH1/IDH2-TET2 axis is revealed as a targetable vulnerability in AML. Thus, epigenetic control by a MYC-TFEB circuit dictates myeloid cell fate and is essential for maintenance of AML.Entities:
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Year: 2021 PMID： 33860275 PMCID： PMC8043621 DOI： 10.1158/2643-3230.BCD-20-0029
Source DB: PubMed Journal: Blood Cancer Discov ISSN： 2643-3230