Loss of EZH2 Reprograms BCAA Metabolism to Drive Leukemic Transformation
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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
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Silencing Bcat1 reduces leukemia initiation, and overexpressing it promotes NRas-driven leukemia initiation even in cells lacking Ezh2 mutations.
“Silencing Bcat1 reduces leukemia initiation, and overexpressing this enzyme promotes NRas-driven leukemia initiation even in cells that lack Ezh2 mutations (28).”
From Metabolic reprogramming and cancer progression (2020) · cites this paper as [28]
In mice, oncogenic NRas cooperates with Ezh2 mutations to produce aggressive leukemias.
“In mice, oncogenic neuroblastoma Ras viral oncogene homolog (NRas) cooperates with mutations in the epigenetic regulator enhancer of zeste homolog 2 (Ezh2) to produce aggressive leukemias.”
From Metabolic reprogramming and cancer progression (2020) · cites this paper as [28]
Ezh2 mutations result in enhanced expression of Bcat1.
“Ezh2 mutations result in enhanced expression of branched-chain amino acid transaminase-1 (Bcat1).”
From Metabolic reprogramming and cancer progression (2020) · cites this paper as [28]
Bcat1 promotes cancer by allowing cells to generate a large leucine pool, which activates mTOR.
“This enzyme promotes cancer by allowing cells to generate a large leucine pool, activating the growth-stimulating mechanistic target of rapamycin (mTOR).”
From Metabolic reprogramming and cancer progression (2020) · cites this paper as [28]
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- Authors
- 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., DeBerardinis, R. J., & Xu, J.
- Affiliations
- Harold C. Simmons Comprehensive Cancer Center (US)
- The University of Texas Southwestern Medical Center (US)
- University Hospital of Basel (CH)
- University of Florida (US)
- Howard Hughes Medical Institute (US)
- Corresponding author
- Xu, Jian
- ORCID
- Venue
- Cancer Discovery
- Published
- 2019-09-01
- Volume
- 9
- Issue
- 9
- Pages
- 1228-1247
- ISSN
- 2159-8274 (ISSN-L)
- 2159-8290
- PMC
- PMC6726547
- OpenAlex
- W2950184715
- Cited by
- 173
- References
- 70
- Citations by year
- 2026: 15 · 2025: 25 · 2024: 26 · 2023: 20 · 2022: 29 · 2021: 29 · 2020: 24 · 2019: 5
- FWCI
- 15.37
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Cancer Discovery (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- American Heart Association (18POST34060219)
- Cancer Prevention and Research Institute of Texas (RP160157)
- NIH (R01DK111430, R01CA230631)
- CPRIT (RR140025, RP180504, RP180826, RP190417)
- Topics
- Health Sciences › Medicine › Hematology › Acute Myeloid Leukemia Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Keywords
- EZH2, NRAS G12D, myeloproliferative neoplasms, myeloid leukemia, leukemic transformation, BCAT1, branched-chain amino acid metabolism, mTOR signaling, EZH1, leukemia-initiating cells, epigenetic reprogramming, metabolic vulnerability, epigenetic vulnerability, cancer metabolism
- MeSH terms
- Enhancer of Zeste Homolog 2 Protein, Amino Acids, Branched-Chain, Transaminases, Animals, Humans, Leukemia, Membrane Proteins, Mutation, Myeloproliferative Disorders, Neoplasm Transplantation, Signal Transduction, GTP Phosphohydrolases, Mice, TOR Serine-Threonine Kinases
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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