Branched Chain Amino Acid Metabolism in Development and Cancer

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dc.contributor.advisorAgathocleous, Michalisen
dc.contributor.committeeMemberDeBerardinis, Ralph J.en
dc.contributor.committeeMemberChung, Stephen S.en
dc.contributor.committeeMemberXu, Jianen
dc.creatorPatrick, McKenzie Tayloren
dc.creator.orcid0000-0001-5891-1649
dc.date.accessioned2024-09-20T22:21:35Z
dc.date.available2024-09-20T22:21:35Z
dc.date.created2022-08
dc.date.issued2022-08
dc.date.submittedAugust 2022
dc.date.updated2024-09-20T22:21:35Z
dc.descriptionThe general metadata -- e.g., title, author, abstract, subject headings, etc. -- is publicly available, but access to the submitted files is restricted to UT Southwestern campus access and/or authorized UT Southwestern users.en
dc.description.abstractDysregulation of branched chain amino acids (BCAAs) and/or the enzymes catalyzing the first step in their catabolism, branched chain amino acid transaminase (BCAT) 1 or 2, are associated with a multitude of diseases. Despite their importance in physiology and pathobiology, in vivo studies examining the roles of BCAT1 and BCAT2 in normal development and cancer are critically lacking. We generated new BCAT1 and/or BCAT2 constitutive or conditional knockout (KO) mice, as well as BCAT1 constitutive or conditional knockin overexpression (OE) mice, and systematically examined the impacts of BCAT1 and/or BCAT2 KO or BCAT1 OE on normal development, hematopoiesis, and leukemia initiation and maintenance in vivo. First, we discovered that loss of BCAT2 but not BCAT1 leads to accumulation of BCAAs and BCKAs, causing morbidity and mortality that can be ameliorated by dietary BCAA restriction. Through proximity labeling proteomics, enzymatic and isotope tracing assays, we provide evidence for the formation of a mitochondrial BCAA metabolon involving BCAT2 and BCKDH, the second enzyme catalyzing the rate-limiting step of BCAA catabolism. Disabling the metabolon contributes to BCAT2-deficiency-induced phenotypes, which can be reversed by BCAT1-mediated BCKA reamination. These findings establish a role for metabolon formation in BCAA metabolism in vivo, and suggest a new strategy to modulate this pathway in diseases involving dysfunctional BCAA metabolism. Next, we determined that BCAT1 is dispensable for normal hematopoiesis and development, but BCAT1 OE increases hematopoietic stem cell frequency and function. BCAT1 expression is significantly increased in human primary AML samples containing FLT3 and AML1-ETO mutations but decreased in AML with MLL abnormalities, raising a fundamental question about how distinct oncogenic drivers create selective metabolic dependencies. Using retroviral and genetic murine leukemia models, we discovered that BCAT1 is required for FLT3-ITD- and AE9a-induced leukemia development and FLT3-ITD leukemia maintenance, whereas BCAT1 OE accelerated FLT3-ITD leukemia progression. In contrast, modulating BCAT1 expression in MLL-AF9 had no effect on leukemia development or maintenance. Our findings establish BCAT1 and BCAA as a metabolic dependency of AML-initiating cells in vivo and uncover new insights into onco-genotype-specific metabolic rewiring as a selective and targetable vulnerability.en
dc.format.mimetypeapplication/pdfen
dc.identifier.oclc1456721146
dc.identifier.urihttps://hdl.handle.net/2152.5/10422
dc.language.isoenen
dc.subjectAmino Acids, Branched-Chainen
dc.subjectDisease Progressionen
dc.subjectLeukemia, Myeloid, Acuteen
dc.subjectTransaminasesen
dc.titleBranched Chain Amino Acid Metabolism in Development and Canceren
dc.typeThesisen
dc.type.materialtexten
local.embargo.lift2027-08-01
local.embargo.terms2027-08-01
thesis.degree.departmentGraduate School of Biomedical Sciencesen
thesis.degree.disciplineCancer Biologyen
thesis.degree.grantorUT Southwestern Medical Centeren
thesis.degree.levelDoctoralen
thesis.degree.nameDoctor of Philosophyen

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UT Southwestern Graduate School of Biomedical Sciences