Germline mutations of PTPN11 (SHP2) in the stem cell microenvironment
干细胞微环境中 PTPN11 (SHP2) 的种系突变
基本信息
- 批准号:10369684
- 负责人:
- 金额:$ 46.29万
- 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 2025-06-30
- 项目状态:未结题
- 来源:
- 关键词:Adrenergic ReceptorBloodBone MarrowBone Marrow CellsCell surfaceCellsClinical ManagementDataDevelopmentDiseaseEmbryonic DevelopmentFaceFundingGenesGerm-Line MutationHematologic NeoplasmsHematopoieticHematopoietic stem cellsHormonesHumanIn VitroJuvenile Myelomonocytic LeukemiaKnock-in MouseKnowledgeLaboratoriesLeadMaintenanceMalignant Childhood NeoplasmMalignant NeoplasmsMediatingMental RetardationMesenchymal Stem CellsMolecularMusMutateMutationMyeloproliferative diseaseNerve FibersNeural CrestNeurogliaNeurotransmittersNoonan SyndromeOsteoblastsPTPN11 genePathogenesisPathogenicityPatientsPeripheral Nervous SystemPreventionPrognosisProtein Tyrosine PhosphataseProteinsRas Signaling PathwayReceptor SignalingResearchRiskRoleSchwann CellsSignal PathwaySignaling MoleculeSpecimenStem cell transplantStructureTestingTherapeutic InterventionTransplantationTreatment outcomeWorkcell typechemokinecongenital heart disordercytokinedevelopmental diseasegain of functionimprovedleukemialeukemogenesismouse modelmutantnerve stem cellnestin proteinnovelnovel therapeutic interventionnovel therapeuticsosteoprogenitor cellpreventrational designstem cellstherapeutic developmenttraffickingtransplantation therapy
项目摘要
Project Summary
Noonan Syndrome (NS), a developmental disorder characterized by congenital heart disease, dysmorphic
facial structures, short stature, and mental retardation, is caused by germline mutations in the genes involved
in the Ras signaling pathway. Patients with NS are at an increased risk of developing leukemia. The
mechanisms underlying the leukemogenesis are not completely understood. NS is mainly (>50%) associated
with germline heterozygous activating mutations in the protein tyrosine phosphatase PTPN11 (SHP2), and NS
patients with PTPN11 mutations have the worst prognosis. Studies from our laboratory and others have
established the causal role of hematopoietic cell intrinsic PTPN11 mutations in the pathogenesis of NS-
associated leukemia. Notably, in the last funding period we discovered that PTPN11 activating mutations
(E76K or D61G) in the bone marrow (BM) stroma, specifically Nestin-expressing and Nestin-expressing cell-
derived mesenchymal stem cells and osteoprogenitors, contributed significantly to the development/
progression of hematological malignancies in mouse models. However, our understanding of the effects of
PTPN11 disease mutations in the BM microenvironment is still incomplete. Our recent pilot data indicate that
PTPN11 activating mutations in the peripheral nervous system (PNS) and other neural crest-derived progeny
in the BM stroma also exert detrimental effects on resident HSCs neural crest-specific PTPN11E76K mutation
knock-in mice (PTPN11E76K/+/Wnt1-Cre+) developed a myeloproliferative neoplasm (MPN), and this malignancy
originated from wild-type hematopoietic stem cells (HSCs). Furthermore, a donor cell-derived MPN (D-MPN)
developed in PTPN11E76K/+/Wnt1-Cre+ mice transplanted with healthy BM cells. The overall objective of this
application is to decipher the cellular and molecular mechanisms by which the PTPN11 mutation in neural
crest-derived cells in the BM stroma induce a MPN. The central hypothesis of the proposal is that the PTPN11
mutation in these microenvironmental cells drives leukemia development by directly and/or indirectly
hyperactivating resident HSCs. We plan to test this hypothesis and accomplish the objective of this application
by pursuing the following three aims. 1). To identify the cell type, protein factors, and/or neurotransmitters that
mediate the leukemogenic effect of PTPN11 activating mutations in the PNS and other neural crest derivatives
in the BM stroma. 2). To determine the molecular mechanisms by which PTPN11 gain-of-function activating
mutations deregulate the activities of the PNS and other neural crest-derived cells. 3). To validate the
pathogenic effects of BM microenvironmental PTPN11 disease mutations with NS patient specimens and
patient-derived cells. The research proposed in this application will not only greatly advance our understanding
of the mechanisms underlying the leukemogenesis in NS, but also inform the rational design of new
therapeutic interventions for preventing leukemia development in NS and improving stem cell transplantation
therapy for NS-associated hematological malignancies.
项目总结
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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CHENG-KUI QU其他文献
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{{ truncateString('CHENG-KUI QU', 18)}}的其他基金
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:
$ 46.29万 - 项目类别:
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
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10561291 - 财政年份:2023
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$ 46.29万 - 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
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10581643 - 财政年份:2022
- 资助金额:
$ 46.29万 - 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:
$ 46.29万 - 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:
$ 46.29万 - 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:
$ 46.29万 - 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:
9174534 - 财政年份:2016
- 资助金额:
$ 46.29万 - 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:
$ 46.29万 - 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
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9327048 - 财政年份:2016
- 资助金额:
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