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

供体造血 DNMT3A 突变对干细胞移植受者的影响

基本信息

  • 批准号:
    10284166
  • 负责人:
  • 金额:
    $ 21.99万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2021
  • 资助国家:
    美国
  • 起止时间:
    2021-09-01 至 2026-08-31
  • 项目状态:
    未结题

项目摘要

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.
项目总结/文摘

项目成果

期刊论文数量(0)
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科研奖励数量(0)
会议论文数量(0)
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Christopher James Gibson其他文献

A Simple Prediction Model of Outcomes after Allogeneic Hematopoietic Stem Cell Transplant (HCT) in Myelodysplastic Syndromes Using HCT-Comorbidity Index, Cytogenetic Risk, and Platelet Count
  • DOI:
    10.1182/blood-2023-185315
  • 发表时间:
    2023-11-02
  • 期刊:
  • 影响因子:
  • 作者:
    Stacey M Frumm;Haesook T. Kim;Amar H Kelkar;Vincent T. Ho;Mahasweta Gooptu;Christopher James Gibson;John Koreth;Roman M. Shapiro;Rizwan Romee;Sarah Nikiforow;Joseph H. Antin;Robert J. Soiffer;Benjamin Rolles;Shai Shimony;Jan Philipp Bewersdorf;Tariq Kewan;Abdulrahman Alhajahjeh;Marlise R. Luskin;Jacqueline S. Garcia;Evan C. Chen
  • 通讯作者:
    Evan C. Chen
<em>DNMT3A</em>-Mutated Stem and Progenitor Cells Contribute to Altered T Cell Activation in Clonal Hematopoiesis
  • DOI:
    10.1182/blood-2023-180180
  • 发表时间:
    2023-11-02
  • 期刊:
  • 影响因子:
  • 作者:
    Ksenia R. Safina;Shawn David;Kyle A. Romine;Kristina D. Mujica;Daniel Ssozi;Jonathan Good;Nurefsan Sariipek;Yoke Seng Lee;Adrienne Parsons;Sarah Bibeau;Adam S. Sperling;Christopher James Gibson;Gabriel K. Griffin;Alexander G. Bick;Antonia Kreso;Jennifer J. Trowbridge;Peter van Galen
  • 通讯作者:
    Peter van Galen
emSTAG2/em Somatic Mutations Are Associated with Specific Dysplastic Megakaryocytic and Myeloid Cell Features in Myelodysplastic Syndrome
emSTAG2/em 体细胞突变与骨髓增生异常综合征中特定的发育异常巨核细胞和髓系细胞特征相关
  • DOI:
    10.1182/blood-2023-187172
  • 发表时间:
    2023-11-02
  • 期刊:
  • 影响因子:
    23.100
  • 作者:
    Waihay J Wong;Rebecca L. Zon;Caleb Ho;Olga Pozdnyakova;Donna S. Neuberg;Elisabeth M Battinelli;Marlise R. Luskin;Zuzana Tothova;Elizabeth A. Morgan;Christopher James Gibson;Benjamin L. Ebert
  • 通讯作者:
    Benjamin L. Ebert
Post Allogeneic Stem Cell Transplant Outcomes Following Response to Hypomethylating Agent Therapy in Myelodysplastic Syndromes Are Predicted By Persistent International Prognostic Scoring System-Molecular Risk
  • DOI:
    10.1182/blood-2023-185220
  • 发表时间:
    2023-11-02
  • 期刊:
  • 影响因子:
  • 作者:
    Stacey M Frumm;Haesook T. Kim;Amar H Kelkar;Vincent T. Ho;Mahasweta Gooptu;Christopher James Gibson;John Koreth;Roman M. Shapiro;Rizwan Romee;Sarah Nikiforow;Joseph H. Antin;Robert J. Soiffer;Benjamin Rolles;Shai Shimony;Jan Philipp Bewersdorf;Tariq Kewan;Abdulrahman Alhajahjeh;Marlise R. Luskin;Jacqueline S. Garcia;Evan C. Chen
  • 通讯作者:
    Evan C. Chen
Clonal Hematopoiesis and Venous Thromboembolism in the UK Biobank
  • DOI:
    10.1182/blood-2023-180764
  • 发表时间:
    2023-11-02
  • 期刊:
  • 影响因子:
  • 作者:
    Becky Zon;Aswin Sekar;Katharine Clapham;Abhishek Niroula;Alexander G. Bick;Christopher James Gibson;Gabriel K. Griffin;Md Mesbah Uddin;Pradeep Natarajan;Benjamin L. Ebert
  • 通讯作者:
    Benjamin L. Ebert

Christopher James Gibson的其他文献

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{{ truncateString('Christopher James Gibson', 18)}}的其他基金

The Impact of Donor Hematopoietic DNMT3A Mutations in Stem Cell Transplant Recipients
供体造血 DNMT3A 突变对干细胞移植受者的影响
  • 批准号:
    10471977
  • 财政年份:
    2021
  • 资助金额:
    $ 21.99万
  • 项目类别:

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