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

Overview

Journal Blood Cancer Discov

Specialties Hematology
Oncology

Date 2021 Apr 16

PMID 33860275

Citations 21

Authors

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 Kaufmann

Anders E Berglund

John L Cleveland

Affiliations

Soon will be listed here.

Abstract

MYC oncoproteins regulate transcription of genes directing cell proliferation, metabolism and tumorigenesis. A variety of alterations drive 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.

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