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

> **NIH NIH K08** · DANA-FARBER CANCER INST · 2021 · $219,904

## Abstract

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...

## Key facts

- **NIH application ID:** 10284166
- **Project number:** 1K08CA263555-01
- **Recipient organization:** DANA-FARBER CANCER INST
- **Principal Investigator:** Christopher James Gibson
- **Activity code:** K08 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $219,904
- **Award type:** 1
- **Project period:** 2021-09-01 → 2026-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10284166

## Citation

> US National Institutes of Health, RePORTER application 10284166, The Impact of Donor Hematopoietic DNMT3A Mutations in Stem Cell Transplant Recipients (1K08CA263555-01). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10284166. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*