2024 - Loss of Ezh2 Activates BCAA Metabolism to Drive Myeloid Transformation

Abstract

Epigenetic regulation and metabolism are highly intertwined, yet little is known whether and how altered epigenetics influences cellular metabolism in cancer progression. We have established a new genetic model of myeloproliferative neoplasm (MPN) by hematopoietic-selective activation of oncogenic Ras (NRasG12D) and inactivation of Ezh2, the histone H3-Lys27 methyltransferase. While NRasG12D+/- alone led to an indolent MPN, Ezh2 loss markedly accelerated disease progression to life-threatening stages, resulting in thrombocytosis, neutrophilia, myelofibrosis, leukemic transformation and mortality. Strikingly, while loss of Ezh1, a homolog of Ezh2, had no effect on hematopoiesis, concurrent inactivation of Ezh1 and Ezh2 with NRasG12D+/- abolished MPN development and myelofibrosis. These results establish Ezh1 as a selective epigenetic vulnerability for MPNs induced by Ezh2-deficiency. Reprogrammed cellular metabolism underlies the progression of various cancers including leukemia. We noted by RNA-seq that Bcat1, the first enzyme catalyzing the transamination of branched-chain amino acids (BCAAs), was aberrantly activated in Ezh2-deficient leukemia-initiating cells (LICs). Bcat1 promoter is enriched with H3K27me3 in HSCs, suggesting that it is epigenetically silenced by Ezh2 in normal hematopoiesis. Furthermore, genetic or pharmacologic inhibition of Bcat1 selectively abrogated the clonogenic activity of Ezh2-deficient LICs and the leukemogenic potential in transplanted recipients, highlighting a metabolic dependency for Ezh2-mutant myeloid neoplasms. Follow-up isotope tracing and metabolic flux analyses ex vivo and in vivo established critical roles of Bcat1 and BCAAs in MPN progression and myeloid transformation. Collectively, our results not only validate Ezh1 as an epigenetic liability for Ezh2-deficient myeloid neoplasms, but also identify a new molecular link between Ezh2, Bcat1 and BCAA metabolism required for myeloid transformation. Since normal HSCs are unaffected by loss of Ezh1 or Bcat1, the selective vulnerabilities raise the possibility of leveraging Ezh1 or BCAA metabolism as targeted therapies to specifically eradicate cancer-initiating cells.