Cross-talk mechanisms between RUNX1 and inflammatory signals impacting functions of stem and progenitors in Familial Platelet Disorder.
RUNX1 和炎症信号之间的串扰机制影响家族性血小板疾病中干细胞和祖细胞的功能。
基本信息
- 批准号:10387899
- 负责人:
- 金额:$ 4.68万
- 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:2022-04-25 至 2025-04-24
- 项目状态:未结题
- 来源:
- 关键词:3-DimensionalAcute Myelocytic LeukemiaAddressAgeApoptosisAspirate substanceAttenuatedAutomobile DrivingBinding SitesBiological AssayBiologyBlood Coagulation DisordersBlood PlateletsBone MarrowBone Marrow CellsBone Marrow DiseasesBone Marrow TransplantationCRISPR/Cas technologyCell CountCell CycleCellsClassification SchemeClinicalCoculture TechniquesDNADataDefectDevelopmentDiagnosisDifferentiation and GrowthDiseaseEczemaEventExtracellular FluidFailureFamilial Platelet DisorderFamilyFlow CytometryFrightFunctional disorderGene Expression ProfilingGenesGeneticGenetic TranscriptionGerm-Line MutationGoalsGrowthGuidelinesHematopoiesisHematopoieticHematopoietic stem cellsHumanHypersensitivityImpairmentIn VitroIndividualInflammationInflammatoryInflammatory Response PathwayInheritedKnock-outKnowledgeLabelLaboratoriesLeadLifeLigandsMeasuresMediatingMegakaryocytesMethodsModelingMonitorMusMutateMutationMyelogenousMyeloproliferative diseaseOutcome StudyPathway AnalysisPathway interactionsPatientsPharmacologyPredispositionPreventionPreventive careRUNX1 geneRiskRoleSeriesSignal TransductionSkinSolid NeoplasmStainsStressStromal CellsStudy modelsSymptomsSyndromeTestingTransplantationUp-RegulationWestern BlottingWild Type MouseWorld Health Organizationbonecancer predispositioncytokineexperimental studyfallshematopoietic differentiationimprovedin vivoin vivo evaluationinhibitorleukemiamesenchymal stromal cellmouse modelnew therapeutic targetperipheral bloodpremalignantprogenitorprotein functionself-renewalskin hypersensitivitystemstem cell growthstem cellstranscription factortranscriptome
项目摘要
PROJECT SUMMARY
Germline cancer predispositions are well established for solid tumors. Once thought to be a rare event,
predispositions to myeloid malignancies are now included in the latest leukemia classification scheme from the
World Health Organization. Thus, more patients are expected to be recognized as carriers which can create a
constant fear of developing leukemia in their families. Given the best treatment is prevention, understanding the
important factors in transitioning from pre-malignant to overt disease stage is fundamental in establishing
guidelines for monitoring and treatment of such patients. Of many leukemia predisposition syndromes, we focus
on familial platelet disorders (FPD) caused by monoallelic RUNX1 germline mutations in. RUNX1-mutations in
FPD lead to bleeding disorders, lower counts and dysfunction of platelets. FPD is one of the most common forms
of inherited myeloid malignancies, and patients have ~40% life-long chance of developing leukemia at median
age of 33 years. The transition to overt leukemia is accompanied by acquisition of secondary mutations, though
the complete mechanism of disease transformationis unknown. Intriguingly, FPD patients manifest with different
allergies such as skin eczema, indicating the possible role of increased inflammation in driving leukemia
development. Therefore, we propose that inflammatory stress facilitates leukemia initiation and progression in
FPD. To test this, we performed series of experiments using primary FPD bone marrow cells. We observed that
FPD hematopoietic stem and progenitors (HSPCs) show myeloid biased differentiation and increased colony
formation ability, while fall behind in megakaryocyte differentiation. Single cell transcriptome analysis of healthy
and FPD bone marrow cells confirmed the skewed differentiation of progenitors and identified enrichment of
inflammatory response pathways in FPD compared to healthy stem cells. Consistently, we found upregulation
of inflammatory cytokines in the bone marrow niche, including from mesenchymal stromal cells. Therefore, I
hypothesize that a cross-talk between RUNX1-mutations mediated changes in HSPCs and inflammatory
microenvironment promotes myeloid growth and differentiation defects in FPD stem and progenitor
cells. To address this hypothesis, in Aim 1, I will evaluate the impact of inflammatory stress on growth and
differentiation of FPD and healthy HSPCs. I will use the genetic or pharmacological inhibition approaches to
dissect the mechanism by which inflammatory stress impacts the functions of FPD HSPCs. Then, I will identify
whether these effects are directly regulated by RUNX1 using CUT&Tag experiments. In Aim 2, I will determine
the effect of RUNX1-mutated bone marrow stromal cells on the function of FPD and healthy HSPCs using newly
established 3D co-culture methods. Then, I will use a unique mouse model with germline Runx1-hetrozygous
mutation to determine the role of bone marrow niche on stem cell growth and differentiation defects. The
outcomes of this study will improve the existing knowledge of disease biology and contribute to my long-term
goal of identifying new targeted therapies for the treatment and even attenuating disease initiation.
项目总结
胚系癌症的易感性对于实体瘤来说是确定的。曾经被认为是罕见的事件,
髓系恶性肿瘤的易感性现在包括在最新的白血病分类方案中
世界卫生组织。因此,预计会有更多的患者被确认为携带者,这可能会创造一个
在他们的家庭中不断地害怕发展成白血病。考虑到最好的治疗是预防,理解
从癌前阶段向显性疾病阶段过渡的重要因素是建立
监测和治疗这类患者的指南。在许多白血病易感综合征中,我们关注的是
单等位基因RUNX1胚系突变引起的家族性血小板紊乱(FPD)RUNX1-突变
FPD会导致出血性疾病、血小板计数减少和功能障碍。FPD是最常见的形式之一
遗传性髓系恶性肿瘤,患者一生中患白血病的几率约为40%
现年33岁。然而,向临床白血病的转变伴随着继发性突变的获得。
疾病转化的完整机制尚不清楚。有趣的是,FPD患者表现出不同的症状
过敏,如皮肤湿疹,表明炎症增加可能是导致白血病的原因
发展。因此,我们认为炎症应激促进白血病的发生和发展。
法兰克福警局。为了验证这一点,我们使用原代FPD骨髓细胞进行了一系列实验。我们观察到
FPD造血干/祖细胞表现为髓系偏向分化和集落增多
形成能力差,而在巨核细胞分化方面落后。健康人群单细胞转录组分析
和FPD骨髓细胞证实了祖细胞的偏向分化,并确认了对
与健康干细胞相比,FPD中的炎症反应途径。始终如一地,我们发现了上调
包括来自间充质基质细胞在内的骨髓壁龛中的炎性细胞因子。因此,我
假设RUNX1突变之间的串扰介导HSPC的变化和炎症
微环境促进FPD干/祖细胞髓系生长和分化缺陷
细胞。为了解决这一假设,在目标1中,我将评估炎性应激对生长和
FPD与健康HSPC的鉴别。我将使用基因或药物抑制方法来
剖析炎症应激影响FPD-HSPC功能的机制。然后,我会找出
这些效应是否由RUNX1通过Cut&Tag实验直接调节。在目标2中,我将决定
RUNX1基因突变骨髓基质细胞对FPD和健康HSPC功能的影响
建立了3D共培养方法。然后,我将使用一种独特的小鼠模型和生殖系RUNX1-hetrozygous
突变以确定骨髓微环境对干细胞生长和分化缺陷的作用。这个
这项研究的结果将提高现有的疾病生物学知识,并有助于我的长期
目标是为治疗确定新的靶向疗法,甚至减轻疾病的始发。
项目成果
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Mona MohammadHosseini其他文献
Mona MohammadHosseini的其他文献
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{{ truncateString('Mona MohammadHosseini', 18)}}的其他基金
Cross-talk mechanisms between RUNX1 and inflammatory signals impacting functions of stem and progenitors in Familial Platelet Disorder.
RUNX1 和炎症信号之间的串扰机制影响家族性血小板疾病中干细胞和祖细胞的功能。
- 批准号:
10612783 - 财政年份:2022
- 资助金额:
$ 4.68万 - 项目类别:
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