Loss of EZH2 Reprograms BCAA Metabolism to Drive Leukemic Transformation

Zhimin Gu, Yuxuan Liu, Feng Cai, McKenzie Patrick, Jakub Zmajkovic, Hui Cao, Yuannyu Zhang, Alpaslan Tasdogan, Mingyi Chen, Le Qi, Xin Liu, Kailong Li, Junhua Lyu, Kathryn E. Dickerson, Weina Chen, Min Ni, Matthew E. Merritt, Sean J. Morrison, Radek C. Skoda, Ralph J. DeBerardinisJian Xu

Research output: Contribution to journalArticle

15 Scopus citations

Abstract

Epigenetic gene regulation and metabolism are highly intertwined, yet little is known about whether altered epigenetics influence cellular metabolism during cancer progression. Here, we show that EZH2 and NRASG12D mutations cooperatively induce progression of myeloproliferative neoplasms to highly penetrant, transplantable, and lethal myeloid leukemias in mice. EZH1, an EZH2 homolog, is indispensable for EZH2-deficient leukemia-initiating cells and constitutes an epigenetic vulnerability. BCAT1, which catalyzes the reversible transamination of branched-chain amino acids (BCAA), is repressed by EZH2 in normal hematopoiesis and aberrantly activated in EZH2-deficient myeloid neoplasms in mice and humans. BCAT1 reactivation cooperates with NRASG12D to sustain intracellular BCAA pools, resulting in enhanced mTOR signaling in EZH2-deficient leukemia cells. Genetic and pharmacologic inhibition of BCAT1 selectively impairs EZH2-deficient leukemia-initiating cells and constitutes a metabolic vulnerability. Hence, epigenetic alterations rewire intracellular metabolism during leukemic transformation, causing epigenetic and metabolic vulnerabilities in cancer-initiating cells. SIGNIFICANCE: EZH2 inactivation and oncogenic NRAS cooperate to induce leukemic transformation of myeloproliferative neoplasms by activating BCAT1 to enhance BCAA metabolism and mTOR signaling. We uncover a mechanism by which epigenetic alterations rewire metabolism during cancer progression, causing epigenetic and metabolic liabilities in cancer-initiating cells that may be exploited as potential therapeutics.See related commentary by Li and Melnick, p. 1158.This article is highlighted in the In This Issue feature, p. 1143.

Original languageEnglish (US)
Pages (from-to)1228-1247
Number of pages20
JournalCancer discovery
Volume9
Issue number9
DOIs
StatePublished - Sep 1 2019

ASJC Scopus subject areas

  • Oncology

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    Gu, Z., Liu, Y., Cai, F., Patrick, M., Zmajkovic, J., Cao, H., Zhang, Y., Tasdogan, A., Chen, M., Qi, L., Liu, X., Li, K., Lyu, J., Dickerson, K. E., Chen, W., Ni, M., Merritt, M. E., Morrison, S. J., Skoda, R. C., ... Xu, J. (2019). Loss of EZH2 Reprograms BCAA Metabolism to Drive Leukemic Transformation. Cancer discovery, 9(9), 1228-1247. https://doi.org/10.1158/2159-8290.CD-19-0152