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Our research focuses on decoding the role of metabolites and their genetic effectors in the tumor microenvironment of hematologic malignancies. We utilize a combination of functional genomics, metabolomics, circuit mapping, and optogenetics approaches to systematically uncover critical dietary and neuronal activities that regulate stem and progenitor cell development and identify key drug targets to treat hematologic malignancies.

Together, the Zhang laboratory recently uncovered a series of critical metabolites in the tumor microenvironment, including acetylcholine and pyridoxal, and their genetic effectors as novel regulators of hematologic malignancies. We identified the cholinergic receptor muscarinic 4 (CHRM4) as a novel regulator of early erythroid progenitor self-renewal and a therapeutic target for myelodysplastic syndromes (MDS). Our research uncovered the hematopoietic arc as a novel neuronal activity based regulatory mechanism of hematopoietic stem and progenitor cell self-renewal. We also identified the vitamin B6 pathway as a nutritional and metabolic dependency in acute myeloid leukemia (AML) that coordinates nucleotides and putrescine metabolism specifically required for leukemia maintenance. Our research uncovered the vitamin B6 pathway as a pharmacologically actionable target for the treatment of leukemia with minimal myelosuppression effect. Through collaboration with medicinal chemists at our spin-off company, we are building pharmacological approaches at the pharmaceutical industry level to target these novel regulators and translating our discoveries into first-in-class therapeutics, and our findings will help treat devastating hematologic malignancies, including refractory anemia, myelodysplasia and leukemia.