TFEB links MYC signaling to epigenetic control of myeloid differentiation and acute myeloid leukemia

Yun, S. et al. (2021) TFEB links MYC signaling to epigenetic control of myeloid differentiation and acute myeloid leukemia. Blood Cancer Discovery, 2(2), pp. 162-185. (doi: 10.1158/2643-3230.bcd-20-0029) (PMID:33860275) (PMCID:PMC8043621)

[img] Text
240445.pdf - Accepted Version
Restricted to Repository staff only until 21 December 2021.

17MB

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.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Murphy, Professor Daniel
Authors: Yun, S., Vincelette, N. D., Yu, X., Watson, G. W., Fernandez, M. R., Yang, C., Hitosugi, T., Cheng, C.-H., Freischel, A. R., Zhang, L., Li, W., Hou, H., Schaub, F. X., Vedder, A. R., Cen, L., McGraw, K. L., Moon, J., Murphy, D. J., Ballabio, A., Kaufmann, S. H., Berglund, A. E., and Cleveland, J. L.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cancer Sciences
Journal Name:Blood Cancer Discovery
Publisher:American Association for Cancer Research
ISSN:2643-3230
ISSN (Online):2643-3249
Published Online:21 December 2020
Copyright Holders:Copyright © 2020 American Association for Cancer Research
First Published:First published in Blood Cancer Discovery 2(2): 162-185
Publisher Policy:Reproduced in accordance with the publisher copyright policy

University Staff: Request a correction | Enlighten Editors: Update this record