Projects

Pursue novel curative therapies for hematological disorders by advancing understanding of hematopoiesis, stem cell biology, and the pathogenesis of hematological malignancies

Metabolic controls on hematopoietic stem cell fate

The aggregate of cell fate decisions made by an organism’s hematopoietic stem cells (HSCs), together with the lineage specification of progenitor and precursor cells, determines the quality and quantity of hematopoietic activity. Increasing evidence indicates that cellular metabolism plays a critical role in HSC self-renewal; however, the precise manner in which distinct metabolic states influence HSC fate remains unclear. We employ genetic models, metabolic assessments, and single-cell approaches to elucidate the metabolic cues that coordinate HSC fate decisions, with a particular focus on mitochondrial metabolism. In collaboration with Dr. Charles Lin’s laboratory at Massachusetts General Hospital and the imaging facilities at Einstein, we have developed intravital imaging methods to track individual HSCs in the bone marrow of living mice under both steady-state and transplantation conditions. These innovations also enable a deeper understanding of the physiological mechanisms by which cell-to-cell communication within the bone marrow microenvironment modulates HSC function, thereby informing strategies to rejuvenate healthy hematopoiesis in aging individuals. The insights gained from delineating the metabolic requirements of hematopoietic homeostasis are poised to have a substantial impact on HSC research, as well as on clinical practice and the treatment of hematological diseases.

Dissecting the canonical and non-canonical functions of TET in HSCs and hematologic disorders

Myelodysplastic syndrome (MDS) is a disease characterized by disrupted hematopoietic homeostasis arising from abnormal function of HSCs and progenitor cells, and it is often incurable with current therapies. TET2 mutations are among the most frequent genetic alterations in MDS. While proper control of gene expression programs in HSCs by TET2 is essential for maintaining homeostasis, the precise molecular mechanisms remain incompletely understood. This project dissects the molecular requirements of TET2 in HSCs and hematological disorders using genetically modified Tet2 catalytic mutant and knockout mouse models. It will enable profiling of endogenous and physiologically relevant Tet2 functions through comparative epigenomic and transcriptomic analyses, together with hematologic analyses, during normal hematopoiesis and the abnormal trajectories leading to MDS. In collaboration with Dr. Meeld Dawlaty at Einstein, we will reveal novel TET-family–mediated gene regulation in HSCs and embryonic hematopoiesis and will explore targeting these TET2 functions in developing MDS therapeutics.

Mitochondrial alterations by aberrant NPM1 to the pathogenesis of hematological malignancies

Survival rates for patients with MDS have not improved despite ongoing efforts to identify key pathogenic genetic events. In this study, we clarify aberrant nucleophosmin 1 (NPM1) contributions to hematologic disease, with particular emphasis on mitochondrial fitness and inflammasome activation. Metabolic reprogramming in energy pathways, a hallmark of leukemias, plays a critical role in mediating chemoresistance, thereby presenting a potential therapeutic vulnerability. These insights into the multi-omics determinants of hematopoietic homeostasis—crucial for preventing aging—are poised to influence the treatment landscape for MDS, acute myeloid leukemia (AML), and other hematologic malignancies.

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