The University of Texas Southwestern Medical Center
Project Term: July 1, 2019 - June 30, 2024
The processes that control the progression of myeloproliferative neoplasms to leukemic transformation remain largely unknown. We have developed genetic mouse models that recapitulate leukemia progression in humans. We aim to discover new regulators and pathways controlling the propagation of leukemia stem cells as targetable vulnerabilities. Our study promises to provide critical insights into developing new and generalizable therapies to selectively eliminate leukemia stem cells.
This project explores the connection between metabolism, epigenetics, and leukemia. Myeloproliferative neoplasms (MPNs) are blood cancers characterized by gene mutations in hematopoietic stem cells (HSCs). A fear of many patients is the progress from a less severe MPN to an aggressive form of acute leukemia. The processes that control this progression remain unknown; however, my team aims to explore the correlation between disease progression and the epigenetic alteration of certain genes. Epigenetics is the study of biological processes that switch genes on and off, which are caused by modifications of the DNA and/or surrounding proteins. EZH2 is a frequently altered epigenetic factor in blood cancer, and its mutations are associated with worse outcomes in MPN patients. To decipher the pathological role of EZH2, we developed a mouse model containing mutations of EZH2 and another oncogenic protein, NRAS. While mutant NRAS alone led to indolent MPNs, concurrent EZH2 and NRAS mutations accelerated disease progression to an acute leukemia phase. We discovered branched-chain amino acid (BCAA) metabolism as the most activated metabolic pathway in EZH2-mutant stem cells. BCAT1, the first enzyme catalyzing BCAA metabolism, is aberrantly activated in EZH2-mutant MPNs. Our preliminary data shows that inhibition of BCAT1 may be an effective way to reduce the pathological consequences of EZH2-mutant cells. Our findings establish the connection between EZH2 dysregulation and altered metabolism in cancer: a new link between altered epigenetics and metabolism in leukemia progression. Our goal is to uncover the biological mechanisms controlling the metabolic liabilities of leukemia stem cells during leukemia progression. We will determine the role of BCAT1 and BCAAs in EZH2 deficient cells using our unique MPN mouse model and sophisticated metabolic assays. We will also determine if BCAT1 inhibition impairs leukemia growth in laboratory models. We hypothesize that EZH2 mutations induce metabolic rewiring by activating BCAA metabolism and that BCAT1 inhibition selectively eradicates leukemia cells by disabling this metabolic liability. If successful, this work will validate a new metabolic vulnerability for patients carrying EZH2 mutations. Because normal HSCs are unaffected by BCAT1 inhibition, this raises the prospect of leveraging BCAAs as a targeted therapy to specifically eradicate mutant cells without affecting normal cells. Our study promises to provide critical insights into developing new and generalizable therapies to selectively eliminate leukemia stem cells.