Divisions of Hematology & Oncology

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Research

The goal of my research program is to identify novel genes whose genetic/pharmacologic blockade may selectively prevent graft-versus-host disease (GvHD) while maintaining or enhancing graft- versus-leukemia (GvL) effects (aka anti-leukemia activities of donor graft).

Allogeneic hematopoietic cell transplantation (allo-HCT) is the only curative treatment for patients with relapsed/refractory leukemia and marrow failure states such as myelodysplasia and aplastic anemia. The therapeutic benefits of allo-HCT for these patients depend on GvL effects mediated by mature T cells present in the donor graft. Unfortunately, the same donor T cells that mediate the beneficial GvL effect can also cause GvHD. Both GvHD and GvL occur when T cells transplanted from a non-identical donor (the graft) recognize the transplant recipient (the host) and tumors as foreign, thereby initiating an immune reaction in the transplant recipient. Because of a strong association between GvHD and GvL, these two donor T cell-mediated immunologic effects of allo-HCT are difficult to separate. Thus, finding a means to harness the GvL activity of T cells while eliminating their tendency to cause GvHD is a major clinical goal in the allo-HCT field.

To achieve this goal, we have three distinct but closely related projects.

1. Modulation of immune cell trafficking to GvHD target organs vs leukemia cells by targeting interferon gamma receptor and integrins.

2. Role of JAK-STAT signaling in GvHD and tissue restoration.

3. Genome-wide CRISPR/Cas9 screens: The mechanisms by which allogeneic donor T cells differentially modulate GvHD and GvL remain largely unknown. This gap in our mechanistic understanding hinders our ability to specifically prevent/treat GvHD. We hypothesize that the genes we identify as being differentially associated with donor T cells that infiltrate tumors versus GvHD organs will be critical targets for the prevention of GvHD without negatively affecting GvL.