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:
- 金额:$ 68.91万
- 依托单位:
- 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:
- 关键词:Acute Myelocytic LeukemiaAddressAdvanced Malignant NeoplasmAffectAgeAllelesBloodBlood TestsBone MarrowCancer ModelCardiovascular DiseasesCell LineCell SurvivalCellsChromatinClinicClonal EvolutionClonal ExpansionClone CellsClustered Regularly Interspaced Short Palindromic RepeatsCoculture TechniquesCounselingDNA MethylationDNMT3a mutationDependenceDisadvantagedDysmyelopoietic SyndromesEngineeringEventGene MutationGenetic ModelsGenetic RecombinationGenomeGenus MenthaGoalsGuidelinesHematopoiesisHematopoieticHematopoietic stem cellsHumanHuman CloningIn VitroIndividualInflammatoryLarge-Scale SequencingMaintenanceMalignant - descriptorMalignant NeoplasmsMediatingModelingMolecularMonitorMorbidity - disease rateMusMutationMyeloproliferative diseaseNon-Hematologic MalignancyNon-MalignantOncogenicOrganismPathologyPhysiologicalPrecancerous ConditionsPrevalenceProcessRiskRisk EstimateRoleSRSF2 geneTechniquesTestingTherapeuticTimeTissuesWorkXenograft procedureacute myeloid leukemia cellcell immortalizationcell transformationcytokinecytotoxicfitnessgenetic testingin vivoinduced pluripotent stem cellinsightleukemialeukemogenesismutantpatient derived xenograft modelpremalignantstressortherapy outcometranscriptometumorigenesis
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。
.
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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Eirini Papapetrou其他文献
Eirini Papapetrou的其他文献
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{{ truncateString('Eirini Papapetrou', 18)}}的其他基金
Mechanisms and targeting of aberrant Gas activation in myeloid neoplasms
骨髓肿瘤中异常气体激活的机制和靶向
- 批准号:
10659809 - 财政年份:2023
- 资助金额:
$ 68.91万 - 项目类别:
Impact of mutational order on molecular mechanisms of oncogenesis
突变顺序对肿瘤发生分子机制的影响
- 批准号:
10375146 - 财政年份:2022
- 资助金额:
$ 68.91万 - 项目类别:
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
- 批准号:
10643995 - 财政年份:2022
- 资助金额:
$ 68.91万 - 项目类别:
Impact of mutational order on molecular mechanisms of oncogenesis
突变顺序对肿瘤发生分子机制的影响
- 批准号:
10620122 - 财政年份:2022
- 资助金额:
$ 68.91万 - 项目类别:
Dissecting splicing factor mutations in iPSCs
剖析 iPSC 中的剪接因子突变
- 批准号:
9893894 - 财政年份:2017
- 资助金额:
$ 68.91万 - 项目类别:
Dissecting splicing factor mutations in iPSCs
剖析 iPSC 中的剪接因子突变
- 批准号:
9317606 - 财政年份:2017
- 资助金额:
$ 68.91万 - 项目类别:
Modeling chromosome 7 loss in Myelodysplasia-iPSCs
骨髓增生异常-iPSC 中 7 号染色体缺失的建模
- 批准号:
9038428 - 财政年份:2014
- 资助金额:
$ 68.91万 - 项目类别:
Modeling chromosome 7 loss in Myelodysplasia-iPSCs
骨髓增生异常-iPSC 中 7 号染色体缺失的建模
- 批准号:
8788296 - 财政年份:2014
- 资助金额:
$ 68.91万 - 项目类别:
Modeling chromosome 7 loss in Myelodysplasia-iPSCs
骨髓增生异常-iPSC 中 7 号染色体缺失的建模
- 批准号:
9234586 - 财政年份:2014
- 资助金额:
$ 68.91万 - 项目类别:
Genetic correction of human beta-thalassemic induced pluripotent stem cells
人β地中海贫血诱导多能干细胞的遗传校正
- 批准号:
8955926 - 财政年份:2012
- 资助金额:
$ 68.91万 - 项目类别:
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