Project 2: Defining the role of megakaryocyte abnormalities in the progression of primary myelofibrosis
项目 2:确定巨核细胞异常在原发性骨髓纤维化进展中的作用
基本信息
- 批准号:10360650
- 负责人:
- 金额:$ 53.51万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2006
- 资助国家:美国
- 起止时间:2006-07-01 至 2023-05-31
- 项目状态:已结题
- 来源:
- 关键词:Abnormal megakaryocyteAcute leukemiaAffectAnimal ModelApoptosisBenignBlood PlateletsBone MarrowBromodomainCXCL11 geneCell CycleCell modelCellsChromatinClinical TrialsCollaborationsCytokine ActivationDefectDevelopmentDifferentiated GeneDiseaseDisease ProgressionDrug TargetingEmperipolesisEpigenetic ProcessEvolutionFailureFibrosisGATA1 geneGene ExpressionGeneticGrowthHematopoiesisHematopoieticHematopoietic stem cellsHumanIL8 geneImpairmentIndividualIndolentInflammatoryInterleukin-8JAK2 geneLCN2 geneLeadLesionLightMDM2 geneMalignant - descriptorMegakaryocytesMorphologyMusMutateMutationMyelofibrosisNuclearPatientsPatternPhasePhenotypePlayPolyploidyPositioning AttributePrimary MyelofibrosisProcessProliferatingRegulationResearchRoleSignal PathwaySignaling MoleculeSpleenTP53 geneTestingTherapeutic InterventionThrombocytopeniaThrombopoietinTransforming Growth Factor alphaTransforming Growth Factor betaTransplantationWorkWorld Health Organizationcell typeclinical investigationcytokinedriver mutationefficacy studyepigenetic therapyexperimental studyin vivoinhibitorinnovationkinase inhibitormanneutrophilnew therapeutic targetnutlin 3overexpressionprogenitorprogramstargeted treatmentthrombocytosis
项目摘要
PROJECT SUMMARY
Prefibrotic myelofibrosis (PrePMF) was formalized in 2016 by the World Health Organization
(WHO) as a new early indolent form of MF which frequently progresses to myelofibrosis (MF) as
well as acute leukemia. Abnormal regulation of megakaryocyte development is a key feature of
both PrePMF and MF. Under normal conditions, committed megakaryocyte progenitors
proliferate to a limited extent and then give rise to small numbers of large, polyploid
differentiated megakaryocytes. However, upon acquisition of mutations in key signaling
molecules, such as MPL, CALR or JAK2, megakaryocyte progenitors expand and promote
thrombocytosis in PrePMF and thrombocytopenia/myelofibrosis in MF. Previous studies have
demonstrated that a deficiency of the critical megakaryocyte transcription factor GATA1 leads a
MF phenotype in mice and that levels of GATA1 are significantly reduced in the bone marrow of
MF patients. We hypothesize that the loss of GATA1 in MF leads to an aberrant gene
expression program which includes increased levels of pro-fibrotic and inflammatory cytokines
such as TGF-β, LNC2 and IL-8, and that these changes drive the transition from Pre-PMF to MF.
In our project, we will first perform a detailed assessment of cytokine secretion by PrePMF and
MF megakaryocytes from animal models and patients and determine if these alterations induce
aberrant megakaryocyte growth and fibrosis (Aim 1). Then we will assess the specific
contributions of TGF-β to the cell cycle of normal and MF hematopoietic stem cells (Aim 2).
Finally, we will use information from Aim 1 and 2, as well as from Projects 1 and 3, to study the
efficacy of drugs that target the microenvironment, malignant hematopoietic stem cells or
epigenetic regulators on MF in animal models. This work is innovative in that no one has
characterized the way that malignant megakaryocytes guide the progression from Pre-PMF, a
relative benign phase, to MF, the final fatal stage of hematopoietic failure in MPNs. Thanks to
the interactions with the other projects and cores of this PPG, we are uniquely positioned to
define the mechanisms by which megakaryocytes affect the transition from PrePMF to PMF and
the contributions of TGF-β, LCN2 and IL8 to disease. Our work is significant in that it will assist
Project 4 in prioritizing clinical trials already in the pipeline for MF and lead to new targeted
therapies for the MPNs.
项目摘要
纤维化前骨髓纤维化(PrePMF)于2016年由世界卫生组织正式确定
(WHO)作为MF的一种新的早期惰性形式,其经常进展为骨髓纤维化(MF),
以及急性白血病巨核细胞发育的异常调节是巨核细胞增殖的一个关键特征。
PrePMF和MF。在正常情况下,定向巨核祖细胞
在有限的范围内增殖,然后产生少量的大型多倍体,
分化的巨核细胞。然而,在获得关键信号传导中的突变后,
分子,如MPL,CALR或JAK 2,巨核细胞祖细胞扩增和促进
PrePMF中的血小板增多和MF中的血小板减少/骨髓纤维化。先前的研究
证明了关键的巨核细胞转录因子GATA 1的缺乏会导致
MF表型的小鼠和GATA 1的水平显着降低,在骨髓中,
MF患者我们推测MF中GATA 1的缺失导致了一个异常的基因
表达程序,其包括增加的促纤维化和炎性细胞因子水平
如TGF-β,LNC 2和IL-8,这些变化驱动了从Pre-PMF到MF的转变。
在我们的项目中,我们将首先通过PrePMF对细胞因子分泌进行详细评估,
MF巨核细胞从动物模型和患者,并确定这些变化是否诱导
异常巨核细胞生长和纤维化(Aim 1)。然后我们将评估具体的
TGF-β对正常和MF造血干细胞的细胞周期的贡献(目的2)。
最后,我们将使用目标1和2以及项目1和3中的信息来研究
靶向微环境、恶性造血干细胞或
表观遗传调节因子在动物模型中对MF的影响。这项工作的创新之处在于,
描述了恶性巨核细胞引导PMF前体进展的方式,
相对良性阶段,MF,MPN造血功能衰竭的最终致命阶段。感谢
与PPG的其他项目和核心的互动,我们处于独特的地位,
确定巨核细胞影响从PrePMF到PMF转变的机制,
TGF-β、LCN 2和IL 8在疾病中的作用。我们的工作意义重大,因为它将有助于
项目4优先考虑已经在进行中的MF临床试验,并导致新的目标
MPN的治疗方法
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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Anna Rita F Migliaccio其他文献
Anna Rita F Migliaccio的其他文献
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{{ truncateString('Anna Rita F Migliaccio', 18)}}的其他基金
The human glucocorticoid receptor and normal and pathological terminal erythroid
人糖皮质激素受体与正常和病理性终末红细胞
- 批准号:
8550819 - 财政年份:2012
- 资助金额:
$ 53.51万 - 项目类别:
The human glucocorticoid receptor and normal and pathological terminal erythroid
人糖皮质激素受体与正常和病理性终末红细胞
- 批准号:
8416617 - 财政年份:2012
- 资助金额:
$ 53.51万 - 项目类别:
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