Adult stem cells must limit their rate of protein synthesis, but the underlying mechanisms remain largely unexplored. Differences in protein synthesis among hematopoietic stem cells (HSCs) and progenitor cells did not correlate with differences in proteasome activity, total RNA content, mRNA content, or cell division rate. However, adult HSCs had more hypophosphorylated eukaryotic initiation factor 4E-binding protein 1 (4E-BP1) and 4E-BP2 as compared with most other hematopoietic progenitors. Deficiency for 4E-BP1 and 4E-BP2 significantly increased global protein synthesis in HSCs, but not in other hematopoietic progenitors, and impaired their reconstituting activity, identifying a mechanism that promotes HSC maintenance by attenuating protein synthesis.

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.

Highlights d Accelerated wound healing promoted by FK506 is independent of calcineurin inhibition d A non-immunosuppressive FK506 analog activates BMP pathway signaling in human cells d Blockade of BMP signaling abolishes acceleration of healing by combination treatment d BMP receptor inhibition prevents stem cell recruitment at wound sites in vivo