Loss of EZH2 Reprograms BCAA Metabolism to Drive Leukemic Transformation.

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 KE; Chen W; Ni M; Merritt ME; Morrison SJ; Skoda RC; DeBerardinis RJ; Xu J

doi:10.1158/2159-8290.CD-19-0152

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Journal article

Loss of EZH2 Reprograms BCAA Metabolism to Drive Leukemic Transformation.

Gu Z Children's Medical Center Research Institute, The University of Texas Southwestern Medical Center, Dallas, Texas.
Liu Y Children's Medical Center Research Institute, The University of Texas Southwestern Medical Center, Dallas, Texas.
Cai F Children's Medical Center Research Institute, The University of Texas Southwestern Medical Center, Dallas, Texas.
Patrick M Children's Medical Center Research Institute, The University of Texas Southwestern Medical Center, Dallas, Texas.
Zmajkovic J Department of Biomedicine, University Hospital Basel, Basel, Switzerland.
Cao H Children's Medical Center Research Institute, The University of Texas Southwestern Medical Center, Dallas, Texas.
Zhang Y Children's Medical Center Research Institute, The University of Texas Southwestern Medical Center, Dallas, Texas.
Tasdogan A Children's Medical Center Research Institute, The University of Texas Southwestern Medical Center, Dallas, Texas.
Chen M Department of Pathology, The University of Texas Southwestern Medical Center, Dallas, Texas.
Qi L Children's Medical Center Research Institute, The University of Texas Southwestern Medical Center, Dallas, Texas.
Liu X Children's Medical Center Research Institute, The University of Texas Southwestern Medical Center, Dallas, Texas.
Li K Children's Medical Center Research Institute, The University of Texas Southwestern Medical Center, Dallas, Texas.
Lyu J Children's Medical Center Research Institute, The University of Texas Southwestern Medical Center, Dallas, Texas.
Dickerson KE Children's Medical Center Research Institute, The University of Texas Southwestern Medical Center, Dallas, Texas.
Chen W Department of Pathology, The University of Texas Southwestern Medical Center, Dallas, Texas.
Ni M Children's Medical Center Research Institute, The University of Texas Southwestern Medical Center, Dallas, Texas.
Merritt ME Department of Biochemistry and Molecular Biology, College of Medicine, University of Florida, Miami, Florida.
Morrison SJ Children's Medical Center Research Institute, The University of Texas Southwestern Medical Center, Dallas, Texas.
Skoda RC Department of Biomedicine, University Hospital Basel, Basel, Switzerland.
DeBerardinis RJ Children's Medical Center Research Institute, The University of Texas Southwestern Medical Center, Dallas, Texas.
Xu J Children's Medical Center Research Institute, The University of Texas Southwestern Medical Center, Dallas, Texas. jian.xu@utsouthwestern.edu.

2019-06-14

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Cancer discovery. - 2019

Enhancer of Zeste Homolog 2 Protein

English 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.

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