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
- 来源:
- 关键词:Acute Myelocytic LeukemiaAdvisory CommitteesAffectAllogenicAreaBiologic CharacteristicBiological AssayBiological ProcessBiologyBiometryBone MarrowCardiovascular DiseasesCaringCellsCharacteristicsClinicalClonal EvolutionClonal ExpansionCollaborationsCommunitiesCyclophosphamideDana-Farber Cancer InstituteDataData ScienceDevelopment PlansDiseaseDisease remissionDonor SelectionDonor personEngraftmentEnvironmentGenesGenomicsGoalsHematologic NeoplasmsHematopoiesisHematopoieticHematopoietic Stem Cell TransplantationHematopoietic stem cellsHistologicImmuneImmune EvasionImmune systemImmunologic SurveillanceImmunologicsImmunologyImpairmentIndividualInflammatoryInterventionInvestigationLeukocytesMediatingMentorshipModalityMutateMutationMyeloid CellsOutcomeOutputPathogenicityPathway interactionsPatientsPatternPhysiciansPopulationRecurrent diseaseRelapseResearchResearch PersonnelResidual stateRiskSamplingScientistShapesSignal TransductionSomatic MutationStem cell transplantT-Cell DevelopmentT-LymphocyteT-Lymphocyte SubsetsTechniquesTestingTimeToxic effectTrainingTransplant RecipientsTransplantationWorkadverse outcomeage relatedbasecancer cellcareercareer developmentcell typecurative treatmentscytokinecytopeniadisorder riskexhaustionexperimental studygraft failuregraft functiongraft vs leukemia effecthematopoietic cell transplantationimprovedimproved outcomeinsightleukemia relapsemutantnovelnovel strategiesnovel therapeutic interventionpost-transplantpressurerelapse risksingle cell technologysuccess
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.
项目摘要/摘要
造血细胞移植是治疗恶性血液病的重要手段。
(HM)。它的成功取决于捐赠者的造血细胞建立长期造血和
免疫介导性消除残留的恶性细胞。克隆性造血(CH)是与年龄相关的
可检测到的体细胞突变改变其生物功能和炎症输出的状态
造血细胞,在非移植人群中与不良后果一致相关。通过
研究了1727对HCT供受者,我发现捐赠者中的CH很常见,而且失活突变
在基因中,DNMT3A是最常见的变化。我的初步数据显示供体DNMT3A-CH是
通过降低HM复发风险,改善全球受者结局,但也
增加了一部分受者移植失败的风险。根据这些数据和已知的函数
在造血细胞中的DNMT3A,我假设供者DNMT3A-CH I在HCT受者中观察到的效果
是由于DNMT3A突变的长期造血干细胞植入和随后的功能改变
在成熟的DNMT3A突变的白细胞亚群中,特别是T细胞。为了检验这一假设,我提出了以下建议
目的有二:(1)研究DNMT3A-CH对HCT后正常和受损造血功能的影响。这就做
使用基因组、免疫表型和单细胞技术来定义特征,包括细胞
移植到受体体内的供体DNMT3A突变的隔室。然后我将专注于阐明生物学
供体DNMT3A-CH受者发生移植物衰竭的风险。(2)界定DNMT3A-CH在供体-
移植后植入的T细胞。我将使用基因组、免疫表型和单细胞技术
检测供体DNMT3A突变对术后受者T细胞组成和功能的影响
特别关注DNMT3A突变如何调节T细胞耗竭的发展。
然后我将专门评估捐赠者T细胞中的DNMT3A突变如何影响免疫逃避的途径
用于急性髓系白血病复发病例。从这些研究中获得的信息将提供
对移植后造血和免疫监测生物学的新见解可能会有深远的影响
供者选择的含义和增强移植物抗白血病效应的策略。与
在拟议的实验中,我概述了一个五年职业发展计划,目标是成为一名
翻译移植研究中的独立调查者。我已经组建了一个全球顾问委员会
公认的造血、移植免疫学和生物统计学专家,提供实验投入
以及在这些领域的具体培训。达纳-法伯癌症研究所,该研究所拥有一项杰出的研究
社区,并且有成功指导独立内科科学家的长期记录,是一个理想的选择
为完成这些实验和实现我的短期和长期职业目标提供环境。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(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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