Germline mutations of PTPN11 (SHP-2) in the stem cell microenvironment
干细胞微环境中 PTPN11 (SHP-2) 的种系突变
基本信息
- 批准号:9174534
- 负责人:
- 金额:$ 39万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2016
- 资助国家:美国
- 起止时间:2016-08-05 至 2020-06-30
- 项目状态:已结题
- 来源:
- 关键词:Acute leukemiaAddressBloodBone MarrowBone Marrow CellsCell surfaceCellsChildhoodCoculture TechniquesDataDevelopmentDiseaseEmbryonic DevelopmentEvolutionFaceFailureGerm-Line MutationGoalsHematopoieticHematopoietic stem cellsHumanJuvenile Myelomonocytic LeukemiaKnock-in MouseKnowledgeLaboratoriesLeadMalignant NeoplasmsMediatingMental RetardationMesenchymal Stem CellsMolecularMusMutateMutationMyeloproliferative diseaseNoonan SyndromePTPN11 genePathogenesisPatientsPlasmaPlayProtein Tyrosine PhosphataseProteinsRiskRoleSignal PathwaySignaling MoleculeStem cell transplantStem cellsStromal CellsStructureSystemTestingTherapeuticTherapeutic InterventionTissuesTransplantationTreatment outcomeWorkbasecell typecongenital heart disorderdesigndevelopmental diseasegain of functionimprovedleukemialeukemogenesismutantnestin proteinnew therapeutic targetnovelstemstem cell niche
项目摘要
Project Summary
Patients with Noonan syndrome (NS), a developmental disorder characterized by congenital heart
disease, dysmorphic facial structures, short stature, and mental retardation, are at an increased risk of
developing leukemias, especially juvenile myelomonocytic leukemia (JMML), a fatal childhood
myeloproliferative neoplasm (MPN). The mechanisms underlying the leukemogenesis are not completely
understood. Lack of such knowledge impedes the development of therapeutic interventions for effectively
controlling leukemic progression in NS and for improving treatment outcomes in NS-associated
leukemias. Germline activating mutations of PTPN11 (encoding SHP2), a protein tyrosine phosphatase
that we previously demonstrated is required for embryogenesis and hematopoietic cell development, are
associated with more than 50% of patients with NS. Studies from our laboratory and others have
established a cell-intrinsic role of PTPN11 mutations in NS and associated leukemias. Intriguingly, our
most recent studies suggest that PTPN11 mutations in the bone marrow (BM) microenvironment can
also induce a profound myeloid malignancy. The objective of the current project is to determine the
cellular and molecular mechanisms by which PTPN11 mutated microenvironmental cells impact resident
hematopoietic stem cells. The central hypothesis of the proposal is that germline PTPN11 mutations in
the BM microenvironment greatly promote the leukemic progression in NS and cause stem cell
transplantation failure. We plan to test this hypothesis and accomplish the objective of this application by
pursuing the following aims. 1). Identify the cellular components and protein factors that mediate the
leukemogenic effects of PTPN11 mutations in the BM microenvironment. 2). Determine the molecular
mechanisms by which PTPN11 mutations change the activities of microenvironmental cells. 3). validate
the pathogenic effects of PTPN11 mutations in NS patient-derived BM microenvironmental cells. This
project will not only greatly advance our understanding of the pathogenesis of NS-associated leukemias,
but also provide a molecular basis for the rational design of new therapeutics targeting the detrimental
microenvironment in NS patients, which may eventually lead to significant improvements in controlling
leukemic progression in NS and in stem cell transplantation therapy for NS-associated leukemias.
项目总结
项目成果
期刊论文数量(0)
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{{ truncateString('CHENG-KUI QU', 18)}}的其他基金
Targeting leukemic stem cells in acute myeloid leukemia
靶向治疗急性髓系白血病的白血病干细胞
- 批准号:
10561291 - 财政年份:2023
- 资助金额:
$ 39万 - 项目类别:
Eradicating leukemic stem cells in juvenile myelomonocytic leukemia
根除幼年粒单核细胞白血病中的白血病干细胞
- 批准号:
10722045 - 财政年份:2023
- 资助金额:
$ 39万 - 项目类别:
Metabolic regulation of stem cell niche development and function
干细胞生态位发育和功能的代谢调节
- 批准号:
10581643 - 财政年份:2022
- 资助金额:
$ 39万 - 项目类别:
Metabolic regulation of stem cell niche development and function
干细胞生态位发育和功能的代谢调节
- 批准号:
10416234 - 财政年份:2022
- 资助金额:
$ 39万 - 项目类别:
Synthetic lethality in leukemic stem cells in juvenile myelomonocytic leukemia
幼年型粒单核细胞白血病干细胞的综合致死率
- 批准号:
10308711 - 财政年份:2020
- 资助金额:
$ 39万 - 项目类别:
Germline mutations of PTPN11 (SHP2) in the stem cell microenvironment
干细胞微环境中 PTPN11 (SHP2) 的种系突变
- 批准号:
10208202 - 财政年份:2016
- 资助金额:
$ 39万 - 项目类别:
Germline mutations of PTPN11 (SHP2) in the stem cell microenvironment
干细胞微环境中 PTPN11 (SHP2) 的种系突变
- 批准号:
10369684 - 财政年份:2016
- 资助金额:
$ 39万 - 项目类别:
Germline mutations of PTPN11 (SHP2) in the stem cell microenvironment
干细胞微环境中 PTPN11 (SHP2) 的种系突变
- 批准号:
10642661 - 财政年份:2016
- 资助金额:
$ 39万 - 项目类别:
Germline mutations of PTPN11 (SHP-2) in the stem cell microenvironment
干细胞微环境中 PTPN11 (SHP-2) 的种系突变
- 批准号:
9327048 - 财政年份:2016
- 资助金额:
$ 39万 - 项目类别:
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