Loss of EZH2 Reprograms BCAA Metabolism to Drive Leukemic Transformation.

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 NRAS^G12D 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 NRAS^G12D to sustain intracellula

SUBMITTER: Gu Z 

PROVIDER: S-EPMC6726547 | biostudies-literature | 2019 Sep

REPOSITORIES: biostudies-literature