Loss of EZH2 Reprograms BCAA Metabolism to Drive Leukemic Transformation

被引：138

作者：

Gu, Zhimin ^{[1
,2
,3
]}

Liu, Yuxuan ^{[1
,2
,3
]}

Cai, Feng ^{[1
]}

Patrick, McKenzie ^{[1
,2
,3
]}

Zmajkovic, Jakub ^{[4
]}

Cao, Hui ^{[1
,2
,3
]}

Zhang, Yuannyu ^{[1
,2
,3
]}

Tasdogan, Alpaslan ^{[1
]}

Chen, Mingyi ^{[5
]}

Qi, Le ^{[1
]}

Liu, Xin ^{[1
,2
,3
]}

Li, Kailong ^{[1
,2
,3
]}

Lyu, Junhua ^{[1
,2
,3
]}

Dickerson, Kathryn E. ^{[1
,2
,3
]}

Chen, Weina ^{[5
]}

Ni, Min ^{[1
]}

Merritt, Matthew E. ^{[6
]}

Morrison, Sean J. ^{[1
,7
]}

Skoda, Radek C. ^{[4
]}

DeBerardinis, Ralph J. ^{[1
,7
]}

Xu, Jian ^{[1
,2
,3
]}

机构：

[1] Univ Texas Southwestern Med Ctr Dallas, Childrens Med Ctr, Res Inst, Dallas, TX 75390 USA

[2] Univ Texas Southwestern Med Ctr Dallas, Dept Pediat, Harold C Simmons Comprehens Canc Ctr, Dallas, TX USA

[3] Univ Texas Southwestern Med Ctr Dallas, Hamon Ctr Regenerat Sci & Med, Dallas, TX USA

[4] Univ Hosp Basel, Dept Biomed, Basel, Switzerland

[5] Univ Texas Southwestern Med Ctr Dallas, Dept Pathol, Dallas, TX USA

[6] Univ Florida, Coll Med, Dept Biochem & Mol Biol, Miami, FL USA

[7] Univ Texas Southwestern Med Ctr Dallas, Howard Hughes Med Inst, Dallas, TX USA

来源：

CANCER DISCOVERY | 2019年 / 9卷 / 09期

关键词：

METHYLTRANSFERASE GENE EZH2; AMINO-ACID-METABOLISM; SOMATIC MUTATIONS; STEM-CELLS; PATHOGENESIS; PROGRESSION; AML; DIFFERENTIATION; PROLIFERATION; MYELOFIBROSIS;

D O I：

10.1158/2159-8290.CD-19-0152

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

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 NRAS(G12D) 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 NRAS(G12D) 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 leuke-miainitiating 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.

引用

页码：1228 / 1247

页数：20

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