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:10642661
- 负责人:
- 金额:$ 45.62万
- 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 CellsBone Marrow NeoplasmsCell surfaceCellsClinical ManagementDataDevelopmentDiseaseEmbryonic DevelopmentFaceFundingGenesGerm-Line MutationHematologic NeoplasmsHematopoieticHematopoietic stem cellsHeterozygoteHormonesHumanIn VitroJuvenile Myelomonocytic LeukemiaKnock-in MouseKnowledgeLaboratoriesMaintenanceMalignant Childhood NeoplasmMalignant NeoplasmsMediatingMental RetardationMesenchymal Stem CellsMolecularMusMutateMutationMyeloproliferative diseaseNerve FibersNeural CrestNeurogliaNeurotransmittersNoonan SyndromeOsteoblastsPTPN11 genePathogenesisPathogenicityPatientsPeripheral Nervous SystemPreventionPrognosisProtein SecretionProtein Tyrosine PhosphataseProteinsRas Signaling PathwayReceptor SignalingResearchRiskRoleSchwann CellsSignal PathwaySignaling MoleculeSpecimenStem cell transplantStructureTestingTherapeutic InterventionTransplantationTreatment outcomeWorkcell typechemokinecongenital heart disordercytokinedevelopmental diseasegain of functionimprovedleukemialeukemogenesismouse modelmutantnestin proteinnovelnovel therapeutic interventionnovel therapeuticsosteoprogenitor cellpreventprotein protein interactionrational 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.
项目摘要
努南综合征(NS),一种以先天性心脏病为特征的发育障碍,畸形
面部结构、身材矮小和智力低下是由相关基因的胚系突变引起的
在RAS信号通路中。患有NS的患者患白血病的风险增加。这个
白血病发生的潜在机制尚不完全清楚。NS主要(>;50%)关联
蛋白酪氨酸磷酸酶PTPN11(SHP2)和NS的生殖系杂合激活突变
PTPN11基因突变的患者预后最差。我们实验室和其他实验室的研究已经
证实了造血细胞固有的PTPN11突变在NS发病机制中的因果作用
相关性白血病。值得注意的是,在上一个资助期,我们发现PTPN11激活突变
(E76K或D61G)在骨髓基质中,特别是表达巢蛋白的细胞和表达巢蛋白的细胞。
来源的间充质干细胞和骨祖细胞对发育做出了重要贡献。
血液系统恶性肿瘤在小鼠模型中的进展。然而,我们对这种影响的理解
PTPN11疾病在骨髓微环境中的突变仍不完全。我们最近的试点数据表明,
PTPN11激活周围神经系统(PNS)和其他神经脊衍生后代的突变
在骨髓基质中,神经脊特异性PTPN11E76K突变也对驻留的HSCs产生不利影响
转基因小鼠(PTPN11E76K/+/WNT1-Cre+)发展为骨髓增生性肿瘤(MPN),这种恶性肿瘤
来源于野生型造血干细胞(HSCs)。此外,一种供体细胞来源的MPN(D-MPN)
在PTPN11E76K/+/Wnt1-Cre+小鼠体内发育,移植健康的BM细胞。这样做的总体目标是
应用于破译神经中PTPN11突变的细胞和分子机制
骨髓间质中的CREST来源的细胞可诱导MPN。该提案的中心假设是PTPN11
这些微环境细胞中的突变直接和/或间接地推动了白血病的发展
高激活的常驻HSCs。我们计划检验这一假设,并实现这一应用程序的目标
通过追求以下三个目标。1)。以确定细胞类型、蛋白质因子和/或神经递质
PTPN11激活的三叉神经节和其他神经脊衍生物突变对白血病的影响
在BM基质中。2)。确定PTPN11功能增益激活的分子机制
突变会破坏三叉神经核和其他神经脊来源细胞的活动。3)。要验证
骨髓微环境PTPN11病突变对NS患者的致病作用
患者来源的细胞。这项申请中提出的研究不仅将极大地促进我们对
NS白血病发生的潜在机制,也为合理设计新的
预防NS患者白血病发展和促进干细胞移植的治疗干预
NS相关性血液系统恶性肿瘤的治疗。
项目成果
期刊论文数量(12)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Extracellular arginine is required but the arginine transporter CAT3 (Slc7a3) is dispensable for mouse normal and malignant hematopoiesis.
- DOI:10.1038/s41598-022-24554-2
- 发表时间:2022-12-17
- 期刊:
- 影响因子:4.6
- 作者:Yan, Yuhan;Chen, Chao;Li, Zhiguo;Zhang, Jing;Park, Narin;Qu, Cheng-Kui
- 通讯作者:Qu, Cheng-Kui
Germline mutations: many roles in leukemogenesis.
- DOI:10.1097/moh.0000000000000596
- 发表时间:2020-06
- 期刊:
- 影响因子:3.2
- 作者:Kevin Chen;R. Kazi;C. Porter;C. Qu
- 通讯作者:Kevin Chen;R. Kazi;C. Porter;C. Qu
Inhibition of the Gab2/PI3K/mTOR signaling ameliorates myeloid malignancy caused by Ptpn11 (Shp2) gain-of-function mutations.
- DOI:10.1038/leu.2016.326
- 发表时间:2017-06
- 期刊:
- 影响因子:11.4
- 作者:Liu W;Yu WM;Zhang J;Chan RJ;Loh ML;Zhang Z;Bunting KD;Qu CK
- 通讯作者:Qu CK
Loss of Ptpmt1 limits mitochondrial utilization of carbohydrates and leads to muscle atrophy and heart failure in tissue-specific knockout mice.
- DOI:10.7554/elife.86944
- 发表时间:2023-09-06
- 期刊:
- 影响因子:7.7
- 作者:Zheng H;Li Q;Li S;Li Z;Brotto M;Weiss D;Prosdocimo D;Xu C;Reddy A;Puchowicz M;Zhao X;Weitzmann MN;Jain MK;Qu CK
- 通讯作者:Qu CK
JMML tumor cells disrupt normal hematopoietic stem cells by imposing inflammatory stress through overproduction of IL-1β.
- DOI:10.1182/bloodadvances.2021005089
- 发表时间:2022-01-11
- 期刊:
- 影响因子:7.5
- 作者:Yan Y;Dong L;Chen C;Bunting KD;Li Q;Stieglitz E;Loh ML;Qu CK
- 通讯作者:Qu CK
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CHENG-KUI QU其他文献
CHENG-KUI QU的其他文献
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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:
$ 45.62万 - 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
- 批准号:
10561291 - 财政年份:2023
- 资助金额:
$ 45.62万 - 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:
$ 45.62万 - 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:
$ 45.62万 - 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:
$ 45.62万 - 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:
$ 45.62万 - 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:
$ 45.62万 - 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:
$ 45.62万 - 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:
$ 45.62万 - 项目类别:
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