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 infl uence 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-defi cient 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 EZH2defi cient myeloid neoplasms in mice and humans. BCAT1 reactivation cooperates with NRAS G12D to sustain intracellular BCAA pools, resulting in enhanced mTOR signaling in EZH2-defi cient leukemia cells. Genetic and pharmacologic inhibition of BCAT1 selectively impairs EZH2-defi cient leukemiainitiating 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.

Multiplexed capture of spatial configuration and temporal dynamics of locus-specific 3D chromatin by biotinylated dCas9

“…ATAC-seq was performed as previously described with modifications [63]. Briefly, 5 × 10 4 G1ER cells were washed twice in PBS and resuspended in 500 μl lysis buffer (10 mM Tris-HCl, 10 mM NaCl, 3 mM MgCl 2 , 0.1% NP-40, pH 7.4).…”

Interrogation of Enhancer Function by Enhanced CRISPR Epigenetic Editing

“…Four weeks after transplantation, the peripheral blood, bone marrow and spleen were assessed for engraftment by flow cytometry. Bloodsmear was performed and stained with May-Grunwald-Giemsa as previously described 63 . The blue stained cells indicated the circulating leukemia cells.…”

An “EZ” Epigenetic Road to Leukemia Stem Cell Metabolic Reprogramming?

“…In this issue, Gu and colleagues describe a novel form of epigenetic and metabolic reprogramming involved in MPNto-leukemia transformation caused by Nras G12D and Ezh2 homozygous deletion ( 3 ). RAS , a small GTPase, is one of the most frequently mutated oncogenes in cancers.…”

“…Different cellular contexts may define the role of EZH2-regulated BCAT1 functions. A, Loss of Ezh2 synergizes with Nras G12D mutation in MPN-to-leukemia transformation to potentiate BCAA synthesis via BCAT1 and trigger downstream mTORC1 signaling(3). B, Loss of Ezh2 can cooperate with Jak2 V617F mutation in the polycythemia vera (PV) to primary myelofibrosis (PMF) transition(7).…”

“…Level or activity changes are indicated by arrows on the right (up, increase; down, decrease). Symbols in gray color indicate possible regulations that were not studied in publications(3,7). The solid black arrows show the directions of metabolic reactions and thickness shows the activity of the reaction.…”