Compartmentalized BCAA Metabolism in Myeloid Leukemia

About This Grant

PROJECT SUMMARY Acute myeloid leukemia (AML) is the deadliest blood cancer characterized by the abnormal function of hematopoietic precursor cells. Leukemic cells acquire metabolic adaptations that initiate transformation or promote the growth of transformed cells. These metabolic alterations can be exploited for diagnosing, monitoring, and treating cancer, but broad strategies to target reprogrammed metabolism are lacking. The challenges are two-fold: 1) identifying metabolic dependencies that are specific to cancer cells, and 2) developing metabolic interventions that selectively target malignant cells while sparing normal tissues. We discovered that BCAT1, the first enzyme catalyzing branched-chain amino acid (BCAA) metabolism in the cytosol, is aberrantly activated in myeloid leukemia. This contrasts with its mitochondrial isozyme BCAT2, which is required for hematopoietic stem cell (HSC) function but dispensable for leukemogenesis. While BCAT1 activation is common in cancer, its oncogenic mechanisms remain elusive, raising a fundamental question about how BCAA metabolism is reprogrammed to meet the metabolic needs of cancer-initiating cells. In preliminary studies, we developed new mouse models, including BCAT1 and BCAT2 conditional knockout and knockin overexpression mice, to analyze the role of BCAT isozymes in hematopoiesis and leukemia. BCAT1 inactivation had no effect on hematopoiesis, whereas its overexpression enhanced HSC self-renewal and accelerated AML development. In contrast, BCAT2 is required for HSC function, but its overexpression had no effect on hematopoiesis. In compartment-specific genetic reconstitution assays, BCAT1-mediated effects on HSCs and leukemogenesis are compartmentdependent, and its cytosolic activity is necessary for producing S-adenosylmethionine (SAM), a universal methyl donor. These findings explain the BCAT1-associated DNA hypermethylation phenotypes in AML patients and reveal a new mechanism of metabolic compartmentalization in regulating the leukemic epigenome. Building on this new framework, this project aims to dissect the functional and mechanistic roles of compartmentalized BCAA metabolism in epigenetic regulation and AML pathophysiology. We hypothesize that BCAT1 promotes myeloid leukemogenesis by controlling compartment-specific BCAA metabolism and SAM-dependent epigenetic processes. We will test this hypothesis by establishing the functional roles of compartmentalized BCAA metabolism in myeloid leukemia and elucidating the mechanistic roles of BCAT1 in controlling SAM-dependent epigenetic processes. While we will prioritize human-based approaches such as AML cell lines and patientderived xenograft (PDX) models, mouse models will be used to assess metabolic regulation and function in vivo. Together, these studies will not only elucidate the mechanistic basis of ‘compartment-specific’ function for BCAT isozymes but also establish a new paradigm for compartment-dependent metabolism-epigenetics crosstalk in leukemia biology. The concepts, tools, and resources from this study will be broadly applicable to developing strategies to target the metabolic liabilities of cancer-initiating cells in hematological cancers and beyond.