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Cancer Discov. 2019 Jun 12. pii: CD-19-0152. doi: 10.1158/2159-8290.CD-19-0152. [Epub ahead of print]

Loss of EZH2 Reprograms BCAA Metabolism to Drive Leukemic Transformation.

Author information

1
Children's Research Institute, UT Southwestern Medical Center.
2
Children's Medical Center Research Institute, UT Southwestern Medical Center.
3
Children's Research Institute, University of Texas Southwestern Medical Center.
4
Department of Biomedicine, University Hospital Basel and University of Basel.
5
Children's Medical Center Research Institute, UT Southwestern.
6
Department of Pathology, UT Southwestern Medical Center.
7
Epigenetics & Mol Carcinogenesis, UT MDACC.
8
Pathology, UT Southwestern Medical Center.
9
Southwestern Medical Center, UT.
10
Department of Biochemistry and Molecular Biology, College of Medicine, University of Florida.
11
Children's Medical Center Research Institute at UTSW, Pediatrics, University of Texas Southwestern Medical Center at Dallas.
12
Department of Biomedicine, Experimental Hematology, University Hospital Basel and University of Basel.
13
Children's Research Institute and the Department of Pediatrics, University of Texas Southwestern Medical Center at Dallas.
14
Children's Medical Center Research Institute, UT Southwestern Medical Center jian.xu@utsouthwestern.edu.

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 (BCAAs), 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 pharmacological 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.

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