Lingbo Zhang

Our research focuses on decoding the role of metabolites, including micronutrients and neurotransmitters, in the tumor microenvironment of hematologic malignancies. We utilize a combination of CRISPR/Cas functional genomics and metabolomics approaches to systematically uncover key metabolites and their genetic effectors, including receptors and metabolic enzymes, to reveal mechanistic insights of and identify key drug targets for 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 cholinergic receptor muscarinic 4 – CHRM4 as a novel regulator of early erythroid progenitor self-renewal and a therapeutic target for myelodysplastic syndrome (MDS). Our research uncovered the Hematopoietic Arc – HematopoArc as a novel nervous system activity based regulatory mechanism of hematopoietic stem and progenitor cell self-renewal. We also identified 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 vitamin B6 pathway as a pharmacologically – actionable target to treat leukemia with minimal bone marrow suppression effect. Through collaborations with medicinal chemists, we are building pharmacological approaches to target these novel regulators, and our findings will help to treat devastating hematologic malignancies, including refractory anemia, myelodysplasia and leukemia.