TY - JOUR
T1 - Loss of EZH2 reprograms BCAA metabolism to drive leukemic transformation
AU - Gu, Zhimin
AU - Liu, Yuxuan
AU - Cai, Feng
AU - Patrick, McKenzie
AU - Zmajkovic, Jakub
AU - Cao, Hui
AU - Zhang, Yuannyu
AU - Tasdogan, Alpaslan
AU - Chen, Mingyi
AU - Qi, Le
AU - Liu, Xin
AU - Li, Kailong
AU - Lyu, Junhua
AU - Dickerson, Kathryn E.
AU - Chen, Weina
AU - Ni, Min
AU - Merritt, Matthew E.
AU - Morrison, Sean J.
AU - Skoda, Radek C.
AU - Deberardinis, Ralph J.
AU - Xu, Jian
N1 - Publisher Copyright:
© 2019 American Association for Cancer Research.
PY - 2019
Y1 - 2019
N2 - 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.
AB - 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.
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U2 - 10.1158/2159-8290.CD-19-0152
DO - 10.1158/2159-8290.CD-19-0152
M3 - Article
C2 - 31189531
AN - SCOPUS:85071786991
SN - 2159-8274
VL - 9
SP - 1228
EP - 1247
JO - Cancer discovery
JF - Cancer discovery
IS - 9
ER -