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The Impact of Donor Hematopoietic DNMT3A Mutations in Stem Cell Transplant Recipients

Award Number: K08CA263555
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP
PERIOD OF PERFORMANCE START DATE: 09/01/2021
PERIOD OF PERFORMANCE END DATE: 07/14/2024

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The Impact of Donor Hematopoietic DNMT3A Mutations in Stem Cell Transplant Recipients - 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.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2025 ( Subtotal = -$31,808 )
2025	2023	DANA-FARBER CANCER INSTITUTE, INC.	450 BROOKLINE AVE	BOSTON	MA	02215	SUFFOLK	USA	Cancer Research Manpower	000	3	10/23/2024	NON-COMPETING CONTINUATION	-$31,808
														Subtotal = -$31,808

Issue Date FY: 2024 ( Subtotal = $0 )
2024	2023	DANA-FARBER CANCER INSTITUTE, INC.	450 BROOKLINE AVE	BOSTON	MA	02215	SUFFOLK	USA	Cancer Research Manpower	000	3	7/11/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2023 ( Subtotal = $219,904 )
2023	2023	DANA-FARBER CANCER INSTITUTE, INC.	450 BROOKLINE AVE	BOSTON	MA	02215	SUFFOLK	USA	Cancer Research Manpower	000	3	8/18/2023	NON-COMPETING CONTINUATION	$219,904
														Subtotal = $219,904

Issue Date FY: 2022 ( Subtotal = $219,904 )
2022	2022	DANA-FARBER CANCER INSTITUTE, INC.	450 BROOKLINE AVE	BOSTON	MA	02115	SUFFOLK	USA	Cancer Research Manpower	000	2	9/1/2022	NON-COMPETING CONTINUATION	$219,904
														Subtotal = $219,904

Issue Date FY: 2021 ( Subtotal = $219,904 )
2021	2021	DANA-FARBER CANCER INSTITUTE, INC.	450 BROOKLINE AVE	BOSTON	MA	02115	SUFFOLK	USA	Cancer Research Manpower	000	1	8/19/2021	NEW	$219,904
														Subtotal = $219,904

Grand Total All Awards = $627,904

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The Impact of Donor Hematopoietic DNMT3A Mutations in Stem Cell Transplant Recipients

Award Number: K08CA263555

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP

PERIOD OF PERFORMANCE START DATE: 09/01/2021

PERIOD OF PERFORMANCE END DATE: 07/14/2024

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