Abstract

Acute myeloid leukemia (AML) is an aggressive blood cancer characterized by high genetic heterogeneity and metabolic plasticity that contribute to treatment resistance and poor clinical outcomes. Increasing evidence now suggests that cancer cells can reprogram their metabolic pathways to support rapid proliferation, redox homeostasis, and survival under stress conditions. One such pathway is mitochondrial one-carbon metabolism, which has emerged as an important regulator of nucleotide biosynthesis and cellular redox balance. A major player in this network is the mitochondrial enzyme methylenetetrahydrofolate dehydrogenase 2 (MTHFD2). Although MTHFD2 is commonly expressed in many cancers, including AML, its precise role in mitochondrial one-carbon metabolism and its contribution to AML biology and therapy resistance remain poorly defined. The goal of this dissertation was to define the biological and therapeutic significance of MTHFD2 in AML and to evaluate the potential of targeting mitochondrial one-carbon metabolism as a strategy to overcome treatment resistance in AML. Using a combination of genetic, metabolic, and pharmacologic approaches, we investigated the functional requirement for MTHFD2 in both normal hematopoiesis and leukemic cell survival in AML. Our genetic studies show that although MTHFD2 is dispensable for normal hematopoiesis, it is critical for AML cell proliferation and disease progression, demonstrating selective metabolic vulnerability in AML. Following this, we performed stable isotope tracing and metabolic profiling, which further demonstrated that MTHFD2 supports de novo purine biosynthesis and mitochondrial NADPH production, thereby maintaining mitochondrial redox homeostasis. Building on these findings, we next assessed the therapeutic potential of targeting MTHFD2 pharmacologically. We show that MTHFD2 inhibition exhibits potent anti-leukemic activity across a large panel of patient-derived AML samples. Importantly, we found that MTHFD2 inhibition synergizes with the FDA-approved AML therapy venetoclax to induce leukemia cell death. Furthermore, targeting MTHFD2 restored venetoclax sensitivity in AML cells that have acquired drug resistance. Collectively, this dissertation establishes MTHFD2 as a key genetically validated, therapeutically targetable metabolic vulnerability that may enhance venetoclax sensitivity in AML and therefore provides a strong rationale for the development of MTHFD2-targeted therapies. Given that MTHFD2 is overexpressed across multiple cancer types, the mechanistic insights and therapeutic strategies described in this dissertation may have broader implications for the development of metabolism-targeted cancer therapies.

Committee Chair

Stephen Sykes

Committee Members

David Pagliarini; David Spencer; Francesca Ferraro; Robert Mecham

Degree

Doctor of Philosophy (PhD)

Author's Department

Biology & Biomedical Sciences (Cancer Biology)

Author's School

Graduate School of Arts and Sciences

Document Type

Dissertation

Date of Award

4-22-2026

Language

English (en)

Author's ORCID

https://orcid.org/0000-0003-2206-557X

Download

Available for download on Friday, April 21, 2028

Included in

Oncology Commons

Share

COinS