Determining the Role and Targeting potential of Serine Metabolism in aggressive sub-types of Acute Myeloid Leukemia

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Project Summary/Abstract (30 lines max): Acute myeloid leukemia (AML) is an aggressive blood cancer that currently ranks as the deadliest form of leukemia in both adults and children. These unsatisfactory outcomes highlight the urgent need to develop more-effective therapies that either replace or improve the effectiveness existing chemotherapies. Metabolic pathways that regulate the synthesis and catabolism of the non-essential amino acid, serine have recently emerged as therapeutic vulnerabilities in several different types of human cancer. We and others recently discovered that certain aggressive sub-types of AML, such as those bearing MLL-rearrangements (MLLR) or internal tandem duplications of the FLT3 genes (FLT3ITD) heavily depend on serine to maintain cell cycling and the differentiation blockade. Specifically, we found that restriction of dietary serine significantly delays disease onset in a mouse model of MLLR-AML, while others have shown that chemical inhibition of serine synthesis impedes MLLR- or FLT3ITD-AML. This proposal aims to address 3 key unanswered questions: 1) How is serine utilized to support AML? Our preliminary data suggest that AML cells utilize serine to supply pools of purines and purine-derivatives such as S-adenosylmethionine (SAM), which are key anabolic precursors needed to drive cell proliferation and maintain gene expression programs, respectively. We will use a combination of metabolomics, transcriptomics and proteomics in genetically engineered mouse (GEM) and patient-derived xenograft (PDX) models of AML to precisely determine how serine is utilized to support AML. 2) What serine-regulatory enzymes support AML and why? Although several enzymes contribute to serine metabolism, we have identified MTHFD2 as a particularly important candidate in AML. Specifically, we have seen that MTHFD2 inhibition promotes the terminal differentiation of MLLR-AML cells and furthermore, MTHFD2 is the most frequently over-expressed enzyme in human cancer. We have now obtained mice bearing floxed alleles of murine Mthfd2, which we will use to determine the importance of Mthfd2 in AML and healthy hematopoiesis. Given that MTHFD2 catalyzes the incorporation of serine-derived carbons into newly synthesized purines and SAM, we will also examine how Mthfd2 deletion impacts purine and SAM levels as well as the downstream cellular processes supported by these metabolites, such as proliferation and gene expression. 3) Can we develop effective serine-targeting therapies in AML? To address this question, we will evaluate therapeutic strategies for limiting serine availability (e.g. simultaneously restricting dietary serine and serine synthesis) or chemically targeting MTHFD2 using liposomal nanoparticle technology in mouse models of AML. Collectively, the results of these studies will provide new insights into the role of serine metabolism and potentially establish a foundation for developing novel therapeutic strategies for the treatment of AML. Moreover, serine metabolism is often deregulated in many tumor settings and thus results from our proposed studies will likely have implications for other forms of human cancers.