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. Kaufmann; Anders E. Berglund; John L. Cleveland

doi:10.1158/2643-3230.BCD-20-0029

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

Oncology

Research output: Contribution to journal › Article › peer-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.

Original language	English (US)
Pages (from-to)	162-185
Number of pages	24
Journal	Blood cancer discovery
Volume	2
Issue number	2
DOIs	https://doi.org/10.1158/2643-3230.BCD-20-0029
State	Published - Mar 1 2021

ASJC Scopus subject areas

General Medicine

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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., ... Cleveland, J. L. (2021). TFEB Links MYC Signaling to Epigenetic Control of Myeloid Differentiation and Acute Myeloid Leukemia. Blood cancer discovery, 2(2), 162-185. https://doi.org/10.1158/2643-3230.BCD-20-0029

Yun, S, Vincelette, ND, Yu, X, Watson, GW, Fernandez, MR, Yang, C, Hitosugi, T, Cheng, CH, Freischel, AR, Zhang, L, Li, W, Hou, H, Schaub, FX, Vedder, AR, Cen, L, McGraw, KL, Moon, J, Murphy, DJ, Ballabio, A, Kaufmann, SH, Berglund, AE & Cleveland, JL 2021, 'TFEB Links MYC Signaling to Epigenetic Control of Myeloid Differentiation and Acute Myeloid Leukemia', Blood cancer discovery, vol. 2, no. 2, pp. 162-185. https://doi.org/10.1158/2643-3230.BCD-20-0029

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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.}",

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doi = "10.1158/2643-3230.BCD-20-0029",

language = "English (US)",

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T1 - TFEB Links MYC Signaling to Epigenetic Control of Myeloid Differentiation and Acute Myeloid Leukemia

AU - Yun, Seongseok

AU - Vincelette, Nicole D.

AU - Yu, Xiaoqing

AU - Watson, Gregory W.

AU - Fernandez, Mario R.

AU - Yang, Chunying

AU - Hitosugi, Taro

AU - Cheng, Chia Ho

AU - Freischel, Audrey R.

AU - Zhang, Ling

AU - Li, Weimin

AU - Hou, Hsinan

AU - Schaub, Franz X.

AU - Vedder, Alexis R.

AU - Cen, Ling

AU - McGraw, Kathy L.

AU - Moon, Jungwon

AU - Murphy, Daniel J.

AU - Ballabio, Andrea

AU - Kaufmann, Scott H.

AU - Berglund, Anders E.

AU - Cleveland, John L.

PY - 2021/3/1

Y1 - 2021/3/1

N2 - 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.

AB - 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.

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

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