Saturday, November 23, 2024
11/23/2024
PROJECT SUMMARY/ABSTRACT Hematopoietic cell transplant (HCT) is an important treatment modality for patients with hematologic malignancy (HM). Its success depends on the ability of donor hematopoietic cells to establish long-term hematopoiesis and immunologically mediated elimination of residual malignant cells. Clonal hematopoiesis (CH) is an age-related condition in which detectable somatic mutations alter the biologic function and inflammatory output of hematopoietic cells, and in non-transplant populations is uniformly associated with adverse outcomes. By studying 1727 HCT donor-recipient pairs, I found that CH in donors is common and that inactivating mutations in the gene DNMT3A are the most frequent alterations. My preliminary data shows that donor DNMT3A-CH is associated with improved global recipient outcomes, mediated by a reduced risk of HM relapse, but also increases the risk of graft failure in a subset of recipients. Based on these data and the known function of DNMT3A in hematopoietic cells, I hypothesize that the effects of donor DNMT3A-CH I observe in HCT recipients are due to engraftment of DNMT3A-mutated long-term hematopoietic stem cells and subsequent altered function in mature DNMT3A-mutant leukocyte subsets, particularly T cells. To test this hypothesis, I propose the following two aims: (1) Determine the effect of DNMT3A-CH on normal and impaired hematopoiesis following HCT. I will use genomic, immunophenotypic, and single-cell technologies to define the characteristics, including cellular compartment, of donor DNMT3A mutations that engraft in recipients. I will then focus on elucidating the biology of graft failure developing in recipients of donor DNMT3A-CH. (2) Define the effect of DNMT3A-CH in donor- engrafted T-cells after transplantation. I will use genomic, immunophenotypic, and single-cell techniques to determine the effect of donor DNMT3A mutations on T-cell composition and function in recipients after transplantation, focusing specifically on how DNMT3A mutations modulate the development of T-cell exhaustion. I will then specifically assess how donor DNMT3A mutations in T cells affect the pathways of immune evasion utilized by relapsing cases of acute myeloid leukemia. The information gained from these studies will provide new insights into the biology of post-transplant hematopoiesis and immune surveillance that could have profound implications for donor selection and strategies to augment the graft-versus-leukemia effect. In concert with the proposed experiments, I have outlined a five-year career development plan aimed at the goal of becoming an independent investigator in translational transplant research. I have assembled an advisory committee of globally recognized experts in hematopoiesis, transplant immunology, and biostatistics, to provide experimental input and specific training in these fields. Dana-Farber Cancer Institute, which harbors an outstanding research community and has a long track record for successful mentorship of independent physician scientists, is an ideal environment for completion of these experiments and realization of my short and long-term career goals.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).
