Acute myeloid leukemia (AML) is the deadliest blood cancer characterized by aberrant proliferation of hematopoietic precursor cells. Disease-causing leukemia stem cells (LSCs) acquire metabolic adaptations to initiate transformation and/or promote growth of cancer cells.

These metabolic alterations has been exploited to diagnose, monitor, and treat cancer; however, successful targeting of rewired cancer metabolism is rare for most cancers including AML. The challenge is two-fold: 1) to identify LSC-specific metabolic dependencies, and 2) to develop effective strategies to therapeutically target LSCs without affecting normal cells. During the prior award, we discovered that aberrant activatio...

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Acute myeloid leukemia (AML) is the deadliest blood cancer characterized by aberrant proliferation of hematopoietic precursor cells. Disease-causing leukemia stem cells (LSCs) acquire metabolic adaptations to initiate transformation and/or promote growth of cancer cells.

These metabolic alterations has been exploited to diagnose, monitor, and treat cancer; however, successful targeting of rewired cancer metabolism is rare for most cancers including AML. The challenge is two-fold: 1) to identify LSC-specific metabolic dependencies, and 2) to develop effective strategies to therapeutically target LSCs without affecting normal cells. During the prior award, we discovered that aberrant activation of BCAT1, an enzyme catalyzing branched-chain amino acid (BCAA) metabolism, drives leukemia transformation and creates metabolic dependencies in LSCs. BCAT1 is also activated in other cancers but distinct mechanisms were described, raising major questions about how BCAA metabolism is rewired and contributes to pathophysiology and therapy outcome of cancer-initiating cells under physiological conditions. Addressing these questions requires advanced disease modeling that recapitulates the landmark events in human cancer progression and discovering the most relevant metabolic vulnerabilities for cancer-initiating cells.

In this project, we aim to elucidate the mechanisms controlling metabolic rewiring of cancer-initiating cells in vivo by focusing on the role of BCAA metabolism in AML development. The central hypothesis is that metabolic rewiring in LSCs creates metabolic dependencies that can be leveraged to selectively eradicate LSCs. We will determine the functional and mechanistic roles of BCAT1 and rewired BCAA metabolism in AML development, and identify LSC-specific metabolic dependencies under physiological conditions. Our studies will open up new opportunities for selective targeting of LSCs, with clinical implications for better management of aggressive blood cancers.

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