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Research Articles

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. DeBerardinis and Jian Xu
Zhimin Gu
1Children's Medical Center Research Institute, The University of Texas Southwestern Medical Center, Dallas, Texas.
2Department of Pediatrics, Harold C. Simmons Comprehensive Cancer Center, and Hamon Center for Regenerative Science and Medicine, The University of Texas Southwestern Medical Center, Dallas, Texas.
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Yuxuan Liu
1Children's Medical Center Research Institute, The University of Texas Southwestern Medical Center, Dallas, Texas.
2Department of Pediatrics, Harold C. Simmons Comprehensive Cancer Center, and Hamon Center for Regenerative Science and Medicine, The University of Texas Southwestern Medical Center, Dallas, Texas.
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Feng Cai
1Children's Medical Center Research Institute, The University of Texas Southwestern Medical Center, Dallas, Texas.
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McKenzie Patrick
1Children's Medical Center Research Institute, The University of Texas Southwestern Medical Center, Dallas, Texas.
2Department of Pediatrics, Harold C. Simmons Comprehensive Cancer Center, and Hamon Center for Regenerative Science and Medicine, The University of Texas Southwestern Medical Center, Dallas, Texas.
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Jakub Zmajkovic
3Department of Biomedicine, University Hospital Basel, Basel, Switzerland.
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Hui Cao
1Children's Medical Center Research Institute, The University of Texas Southwestern Medical Center, Dallas, Texas.
2Department of Pediatrics, Harold C. Simmons Comprehensive Cancer Center, and Hamon Center for Regenerative Science and Medicine, The University of Texas Southwestern Medical Center, Dallas, Texas.
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Yuannyu Zhang
1Children's Medical Center Research Institute, The University of Texas Southwestern Medical Center, Dallas, Texas.
2Department of Pediatrics, Harold C. Simmons Comprehensive Cancer Center, and Hamon Center for Regenerative Science and Medicine, The University of Texas Southwestern Medical Center, Dallas, Texas.
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Alpaslan Tasdogan
1Children's Medical Center Research Institute, The University of Texas Southwestern Medical Center, Dallas, Texas.
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Mingyi Chen
4Department of Pathology, The University of Texas Southwestern Medical Center, Dallas, Texas.
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Le Qi
1Children's Medical Center Research Institute, The University of Texas Southwestern Medical Center, Dallas, Texas.
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Xin Liu
1Children's Medical Center Research Institute, The University of Texas Southwestern Medical Center, Dallas, Texas.
2Department of Pediatrics, Harold C. Simmons Comprehensive Cancer Center, and Hamon Center for Regenerative Science and Medicine, The University of Texas Southwestern Medical Center, Dallas, Texas.
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Kailong Li
1Children's Medical Center Research Institute, The University of Texas Southwestern Medical Center, Dallas, Texas.
2Department of Pediatrics, Harold C. Simmons Comprehensive Cancer Center, and Hamon Center for Regenerative Science and Medicine, The University of Texas Southwestern Medical Center, Dallas, Texas.
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Junhua Lyu
1Children's Medical Center Research Institute, The University of Texas Southwestern Medical Center, Dallas, Texas.
2Department of Pediatrics, Harold C. Simmons Comprehensive Cancer Center, and Hamon Center for Regenerative Science and Medicine, The University of Texas Southwestern Medical Center, Dallas, Texas.
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Kathryn E. Dickerson
1Children's Medical Center Research Institute, The University of Texas Southwestern Medical Center, Dallas, Texas.
2Department of Pediatrics, Harold C. Simmons Comprehensive Cancer Center, and Hamon Center for Regenerative Science and Medicine, The University of Texas Southwestern Medical Center, Dallas, Texas.
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  • ORCID record for Kathryn E. Dickerson
Weina Chen
4Department of Pathology, The University of Texas Southwestern Medical Center, Dallas, Texas.
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Min Ni
1Children's Medical Center Research Institute, The University of Texas Southwestern Medical Center, Dallas, Texas.
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Matthew E. Merritt
5Department of Biochemistry and Molecular Biology, College of Medicine, University of Florida, Miami, Florida.
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  • ORCID record for Matthew E. Merritt
Sean J. Morrison
1Children's Medical Center Research Institute, The University of Texas Southwestern Medical Center, Dallas, Texas.
6Howard Hughes Medical Institute, The University of Texas Southwestern Medical Center, Dallas, Texas.
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Radek C. Skoda
3Department of Biomedicine, University Hospital Basel, Basel, Switzerland.
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Ralph J. DeBerardinis
1Children's Medical Center Research Institute, The University of Texas Southwestern Medical Center, Dallas, Texas.
6Howard Hughes Medical Institute, The University of Texas Southwestern Medical Center, Dallas, Texas.
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Jian Xu
1Children's Medical Center Research Institute, The University of Texas Southwestern Medical Center, Dallas, Texas.
2Department of Pediatrics, Harold C. Simmons Comprehensive Cancer Center, and Hamon Center for Regenerative Science and Medicine, The University of Texas Southwestern Medical Center, Dallas, Texas.
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  • For correspondence: jian.xu@utsouthwestern.edu
DOI: 10.1158/2159-8290.CD-19-0152 Published September 2019
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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

Footnotes

  • Note: Supplementary data for this article are available at Cancer Discovery Online (http://cancerdiscovery.aacrjournals.org/).

  • Cancer Discov 2019;9:1228–47

  • Received February 3, 2019.
  • Revision received May 16, 2019.
  • Accepted June 7, 2019.
  • Published first June 12, 2019.
  • ©2019 American Association for Cancer Research.
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Cancer Discovery: 9 (9)
September 2019
Volume 9, Issue 9
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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. DeBerardinis and Jian Xu
Cancer Discov September 1 2019 (9) (9) 1228-1247; DOI: 10.1158/2159-8290.CD-19-0152

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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. DeBerardinis and Jian Xu
Cancer Discov September 1 2019 (9) (9) 1228-1247; DOI: 10.1158/2159-8290.CD-19-0152
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