Defining the scope and clinical impact of donor CHIP after allogeneic HCT

定义同种异体 HCT 后供体 CHIP 的范围和临床影响

• 批准号: 10218091
• 负责人: Robert Coleman Lindsley
• 金额: $ 57.67万
• 依托单位: DANA-FARBER CANCER INST
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-14 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10218091
• 关键词: Age; Age-Years; Allogenic; Archives; Bar Codes; Biological; Biology; Cardiovascular system; Cells; Characteristics; Clinical; Clonal Evolution; Clone Cells; Cytokine Signaling; Data; Development; Donor Selection; Donor person; Effector Cell; Engraftment; Epigenetic Process; Frequencies; Functional disorder; Genetic; Gold; Hematologic Neoplasms; Hematopoiesis; Hematopoietic; Hematopoietic Neoplasms; Hematopoietic Stem Cell Transplantation; Hematopoietic stem cells; Homologous Transplantation; Human; Immune; Immune System Diseases; Impairment; Infection; Inferior; Inflammatory; Laboratories; Lead; Leukemic Cell; Link; Measures; Mediating; Medical Genetics; Modality; Modeling; Morbidity - disease rate; Mutation; Mutation Detection; Myeloproliferative disease; Non-Malignant; Outcome; Pathology; Patients; Production; Property; Recovery; Recurrent disease; Relapse; Reporting; Risk; Safety; Sampling; Stem Cell Development; Technology; Testing; Time; Transplant Recipients; Transplantation; Universities; Validation; Work; age related; base; chronic graft versus host disease; clinically significant; cohort; curative treatments; cytokine; cytopenia; donor stem cell; fitness; genetic approach; genetic evolution; graft function; graft vs host disease; high risk; immune function; immune reconstitution; immunoregulation; improved; improved outcome; innovation; insight; mortality; next generation sequencing; novel strategies; post-transplant; sequencing platform; stem cell engraftment; stem cells; success; tool; transcriptome; transcriptomics

PROJECT SUMMARY Allogeneic hematopoietic stem cell transplantation (HSCT) involves the transfer of healthy donor hematopoietic cells, including hematopoietic stem cells and mature immune effector cells, to recipients with high-risk hematologic malignancies. The success of HSCT is fundamentally dependent on engraftment of normal donor- derived hematopoiesis. Inadequate graft function can cause a range of complications that impact recipient outcomes, including disease relapse, graft versus host disease, and infection. In preliminary studies, we identified healthy stem cell donors with clonally restricted hematopoiesis, marked by mutations in canonical genetic drivers of myeloid malignancies, where the aberrant clone engrafted in a transplant recipient, underwent selective expansion, and was associated with abnormal hematopoietic function. While rare patients developed donor cell leukemia after long latency, our data suggest that non-malignant outcomes of donor-engrafted clonal hematopoiesis, such as hematopoietic dysfunction or graft versus host disease may be more common and may manifest earlier after transplantation, thereby contributing significantly to transplant-related morbidity. We hypothesize that the presence of clonal hematopoiesis of indeterminate potential (CHIP) is an age-independent predictor of donor hematopoietic fitness that negatively impacts recipient outcome by causing impaired graft function. This proposal combines complementary genetic, functional, and transcriptomic approaches in a large cohort of stem cell donor-recipient pairs to define the impact of donor CHIP on allo HSCT outcomes. In Specific Aim 1, we will determine the frequency and clinical significance of CHIP in a 1911 allogeneic stem cell donors 40 years of age and older (discovery cohort,n=1189; external validation cohort, n=722). To complete this aim, we have developed and validated a highly sensitive sequencing platform for identification of CHIP in donor samples, with >50-fold greater sensitivity than standard next generation sequencing modalities. This work will be closely linked to Specific Aim 2, where we will focus on the subset of donors with clonal mutations to define the efficiency and lineage potential of clonal stem cell engraftment, and the genetic evolution of clones over time. Finally, in Specific Aim 3 we will dissect the functional impact of donor CHIP on immune function in transplant recipients, testing the hypothesis that stem cell clones can perturb inflammatory cytokine production and proper recovery of immune activity via their clonal contribution to mature immune cell subsets. Together, the proposed studies may define a new paradigm of donor-attributable risk in allogeneic HSCT and provide insights into biological mechanisms of clonal dominance and the influence of microenvironmental context on clonal evolution.

项目总结