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Mechanisms and therapeutic implications of human clonal hematopoiesis (CH) mutations

人类克隆造血（CH）突变的机制和治疗意义

基本信息

批准号：
10450238
负责人：
Eirini Papapetrou
金额：
$ 68.91万
依托单位：
ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-06-15 至 2027-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10450238
关键词：
Acute Myelocytic Leukemia Address Advanced Malignant Neoplasm Affect Age Alleles Blood Blood Tests Bone Marrow Cancer Model Cardiovascular Diseases Cell Line Cell Survival Cells Chromatin Clinic Clonal Evolution Clonal Expansion Clone Cells Clustered Regularly Interspaced Short Palindromic Repeats Coculture Techniques Counseling DNA Methylation DNMT3a mutation Dependence Disadvantaged Dysmyelopoietic Syndromes Engineering Event Gene Mutation Genetic Models Genetic Recombination Genome Genus Mentha Goals Guidelines Hematopoiesis Hematopoietic Hematopoietic stem cells Human Human Cloning In Vitro Individual Inflammatory Large-Scale Sequencing Maintenance Malignant - descriptor Malignant Neoplasms Mediating Modeling Molecular Monitor Morbidity - disease rate Mus Mutation Myeloproliferative disease Non-Hematologic Malignancy Non-Malignant Oncogenic Organism Pathology Physiological Precancerous Conditions Prevalence Process Risk Risk Estimate Role SRSF2 gene Techniques Testing Therapeutic Time Tissues Work Xenograft procedure acute myeloid leukemia cell cell immortalization cell transformation cytokine cytotoxic fitness genetic testing in vivo induced pluripotent stem cell insight leukemia leukemogenesis mutant patient derived xenograft model premalignant stressor therapy outcome transcriptome tumorigenesis

项目摘要

PROJECT SUMMARY/ABSTRACT In recent years, large-scale sequencing revealed that the presence of clonally expanded hematopoietic stem/progenitor cells in the bone marrow and blood of healthy individuals is a widespread phenomenon in humans, generally referred to as clonal hematopoiesis (CH). Clonally expanded hematopoietic cells in many instances harbor mutations associated with myeloid malignancies and, importantly, their presence is associated with increased risk of developing myeloid malignancies (myelodysplastic syndrome, MDS and acute myeloid leukemia, AML). Leukemic progression is invariably associated with acquisition of additional mutations by the CH clone and further clonal expansions. CH is thus a premalignant condition that often constitutes the initiating event of leukemogenesis and thus offers a glimpse into the early events of malignant transformation. However, there is a relative scarcity of models to study early events of leukemogenesis, as mice do not develop CH and most human cancer models (immortalized cell lines, patient-derived xenografts) capture advanced cancers. My lab has pioneered the modeling of myeloid malignancies with human induced pluripotent stem cells (iPSCs). We recently developed a model of successive clonal evolution of AML. The overarching goal of this proposal is to investigate the molecular mechanisms underlying the oncogenic effects of CH mutations. In the first Aim we will characterize cell-intrinsic (transcriptome, chromatin accessibility, DNA methylation) and cell-extrinsic (cytokine secretion, differentiation propensity) effects of the 3 most common CH mutations – DNMT3A, TET2 and ASXL1 – using CRISPR-edited isogenic human iPSCs. In the second Aim we will explore the role of cell competition in the clonal advantage of cells harboring CH mutations before and after acquisition of additional mutations. In the third Aim, we will address the question of whether fully transformed AML cells maintain or lose dependency upon the initial CH mutation using engineered mutant alleles reversible via Cre-loxP recombination and testing the effects of correction of the CH mutation on the initiation and maintenance of AML in vitro and in vivo in xenografts. .

项目总结/摘要近年来，大规模测序显示，克隆扩增的造血干细胞的存在，健康个体的骨髓和血液中的干/祖细胞是一种普遍现象，人类，通常称为克隆造血（CH）。克隆扩增的造血细胞在许多一些实例含有与骨髓恶性肿瘤相关的突变，重要的是，它们的存在是与发生骨髓恶性肿瘤（骨髓增生异常综合征，MDS和急性髓性白血病，AML）。白血病进展总是与获得额外的通过CH克隆的突变和进一步的克隆扩增。因此，CH是一种癌前病变，构成了白血病发生的起始事件，因此提供了对恶性肿瘤的早期事件的一瞥。转型然而，研究白血病发生的早期事件的模型相对缺乏，小鼠不会形成CH和大多数人类癌症模型（永生化细胞系，患者来源的异种移植物）捕捉晚期癌症我的实验室率先建立了人类诱导的骨髓恶性肿瘤模型多能干细胞（iPSC）。我们最近开发了一个AML连续克隆进化的模型。这项建议的首要目标是研究潜在的分子机制， CH突变的致癌作用。在第一个目标中，我们将表征细胞内在（转录组，染色质可及性、DNA甲基化）和细胞外源性（细胞因子分泌、分化倾向）的影响。最常见的CH突变-DNMT 3A，TET 2和ASXL 1-使用CRISPR编辑的同基因人类iPSC。在第二个目的是探讨细胞竞争在携带CH的细胞克隆优势中的作用在获得额外突变之前和之后的突变。在第三个目标中，我们将讨论以下问题：完全转化的AML细胞是否维持或失去对初始CH突变的依赖性，通过Cre-loxP重组可逆的工程化突变等位基因，并测试CH 在体外和体内异种移植物中，突变对AML的起始和维持的影响。 .