TFEB Links MYC Signaling to Epigenetic Control of Myeloid Differentiation and Acute Myeloid Leukemia

Seongseok Yun, Nicole D. Vincelette, Xiaoqing Yu, Gregory W. Watson, Mario R. Fernandez, Chunying Yang, Taro Hitosugi, Chia Ho Cheng, Audrey R. Freischel, Ling Zhang, Weimin Li, Hsinan Hou, Franz X. Schaub, Alexis R. Vedder, Ling Cen, Kathy L. McGraw, Jungwon Moon, Daniel J. Murphy, Andrea Ballabio, Scott H. KaufmannAnders E. Berglund, John L. Cleveland

Research output: Contribution to journalComment/debatepeer-review

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 an MYC-TFEB circuit dictates myeloid cell fate and is essential for maintenance of AML. SIGNIFICANCE: Alterations in epigenetic control are a hallmark of AML. This study establishes that a MYC-TFEB circuit controls AML differentiation and epigenetic programs by inducing IDH1/IDH2 and hydroxylation of 5-methylcytosine, that TFEB functions as a tumor suppressor in AML, and that this circuit is a targetable vulnerability in AML.See related commentary by Wu and Eisenman, p. 116.

Original languageEnglish (US)
Pages (from-to)162-185
Number of pages24
JournalCancer discovery
Volume2
Issue number2
DOIs
StatePublished - Mar 1 2021

ASJC Scopus subject areas

  • Oncology

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