Metabolic Profiling of Leukemic Stem Cells in Acute Myeloid Leukemia: Targeting Serine Synthesis Pathways Using Hyperpolarized MRI

• Applicant: Dr. Rabia Shahswar
• Subject Area: Hematology, Oncology
• Term: since 2025
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 558903617

Despite an initial response, many myeloid leukemias become resistant to chemotherapy. New therapeutic strategies and companion biomarkers for acute myeloid leukemia (AML) patients are therefore urgently needed. While the targeting of metabolic pathways represents a promising, novel approach to treating leukemia and to targeting rare cells, including leukemia stem cells (LSCs), exploration into the metabolism of leukemia and LSCs is hampered by the lack of tools for the quantitative assessment of pathway fluxes. Moreover, the role of oxidative stress in leukemia and the stem cell compartment is not well understood. Serine is a critical metabolic intermediate, required for one–carbon (1C) metabolism. Phosphoglycerate dehydrogenase (PHGDH) is the first, rate-limiting enzyme in the de novo serine synthesis pathway (SSP); is overexpressed or genetically amplified in multiple cancers; and was recently found to be a hit in a hematopoietic stemness screen. Recently published studies and extensive preliminary data suggest a novel therapeutic vulnerability in AML that hijacks 1C metabolism and links it to an abundance of carbohydrates in our diet. Utilizing isotopic tracing with NMR and hyperpolarized magnetic resonance (HP MR) to elucidate the metabolic flux in AML cells, the Kharas group found that carbons are shunted away from glycolysis toward the serine synthesis pathway. This altered metabolic flux results in a new dependency for PHGDH in AML. In contrast, normal human cord blood CD34+ cells are resistant to PHDGH inhibition. This altered metabolic reprograming can be targeted. This proposal will develop strategies that leverage such metabolic changes in order to optimize targeting of the SSP, its effect on oxidative stress and understand its role in LSCs. Furthermore, we will characterize leukemia metabolism using novel hyperpolarized magnetic resonance (MR) probes to measure metabolic flux, providing an unprecedented ability to interrogate glycolysis and oxidative stress in living systems. With the successful completion of the proposed aims, we will have developed a novel approach to the study of AML and, more specifically, the role of LSC metabolism in driving disease progression. We will also have annotated a key metabolic pathway, the serine synthesis pathway, and its rate-limiting enzyme PHGDH as therapeutic targets to be exploited. We will apply a novel metabolic imaging strategy in vitro using an innovative hyperpolarized microcoil NMR platform to study key metabolic features of AML and LSCs. Finally, we will extend this work to metabolic imaging in AML, a critical unmet need in the field, to reveal on-target metabolic perturbations in glycolytic generation of HP lactate and oxidative-stress-inhibited generation of HP vitamin C.

• DFG Programme: WBP Fellowship
• International Connection: USA
• Host: Michael Kharas, Ph.D.