@article{eda38dd68d49428185d5e4cb6af2b5ff,
title = "TFEB Links MYC Signaling to Epigenetic Control of Myeloid Differentiation and Acute Myeloid Leukemia",
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.",
author = "Seongseok Yun and Vincelette, {Nicole D.} and Xiaoqing Yu and Watson, {Gregory W.} and Fernandez, {Mario R.} and Chunying Yang and Taro Hitosugi and Cheng, {Chia Ho} and Freischel, {Audrey R.} and Ling Zhang and Weimin Li and Hsinan Hou and Schaub, {Franz X.} and Vedder, {Alexis R.} and Ling Cen and McGraw, {Kathy L.} and Jungwon Moon and Murphy, {Daniel J.} and Andrea Ballabio and Kaufmann, {Scott H.} and Berglund, {Anders E.} and Cleveland, {John L.}",
note = "Funding Information: The authors thank the Flow Cytometry, Molecular Genomics, Tissue, Biostatistics and Bioinformatics, and Analytical Microscopy Cores of the H. Lee Moffitt Cancer Center and Research Institute, and the Comparative Medicine Department of the University of South Florida (USF). The pRRL-puro plasmid was a kind gift from Dr. Johannes Zuber (IMP, Vienna, Austria). This work benefited from data assembled by the ImmGen Consortium, and the authors also thank AML team members of TARGET for providing expression data. This work was supported in part by an LLS-SCOR grant (J.L. Cleveland), by NIH grant CA225680 (T. Hitosugi), by Deutsche Krebsilfe grant 109220 (D.J. Murphy), by F32 grant CA203217 (M.R. Fernandez), by the Cortner-Couch Endowed Chair for Cancer Research from the USF School of Medicine (J.L. Cleveland), by NIH grant K08 CA237627 (S. Yun), by a Research Training Award for Fellows (RTAF) from the American Society of Hematology (ASH; S. Yun), by a Scholar Award from ASH (S. Yun), by a research grant from the Graduate Medical Education at USF (S. Yun), and by NCI Comprehensive Cancer Grant P30-CA076292 to the H. Lee Moffitt Cancer Center and Research Institute. Funding Information: F.X. Schaub reports grants from Swiss National Science Foundation during the conduct of the study. D.J. Murphy reports grants from Puma Biotech and Merck Group outside the submitted work. A. Ballabio reports personal fees from Casma Therapeutics, Inc. outside the submitted work. S.H. Kaufmann reports grants from Takeda Pharmaceuticals outside the submitted work. J.L. Cleveland reports grants from Leukemia & Lymphoma Society during the conduct of the study. No disclosures were reported by the other authors. Publisher Copyright: {\textcopyright} 2021 blood CANCER DISCOVERY. All rights reserved.",
year = "2021",
month = mar,
day = "1",
doi = "10.1158/2643-3230.BCD-20-0029",
language = "English (US)",
volume = "2",
pages = "162--185",
journal = "Blood cancer discovery",
issn = "2643-3230",
publisher = "NLM (Medline)",
number = "2",
}