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:
    9327048
  • 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

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.
项目摘要 努南综合征(NS)患者,一种以先天性心脏病为特征的发育障碍 疾病、畸形的面部结构、身材矮小和智力迟钝, 发展中的白血病,特别是青少年粒单核细胞白血病(JMML),一个致命的童年 骨髓增生性肿瘤(MPN)。白血病发生的机制并不完全 明白缺乏这方面的知识阻碍了治疗干预措施的发展, 控制NS中的白血病进展和改善NS相关性白血病患者的治疗结果 白血病蛋白酪氨酸磷酸酶PTPN11(编码SHP2)的种系激活突变 我们以前证明的是胚胎发生和造血细胞发育所必需的, 与超过50%的NS患者相关。我们实验室和其他机构的研究表明, 建立了PTPN11突变在NS和相关白血病中的细胞内在作用。有趣的是,我们 最近的研究表明,骨髓(BM)微环境中的PTPN11突变可以 也会诱发严重的骨髓恶性肿瘤本项目的目标是确定 PTPN11突变的微环境细胞影响居民的细胞和分子机制 造血干细胞。该提案的中心假设是,生殖系PTPN 11突变在 骨髓微环境极大地促进NS中白血病的进展, 移植失败我们计划通过以下方式来检验这一假设并实现本申请的目标: 追求以下目标。1)。确定细胞成分和蛋白质因子,介导 PTPN11突变在BM微环境中的致白血病作用。2)。测定分子 PTPN11突变改变微环境细胞活性的机制。3)。验证 PTPN11突变在NS患者来源的BM微环境细胞中的致病作用。这 该项目不仅将大大推进我们对NS相关白血病发病机制的理解, 而且还为合理设计针对有害的 NS患者的微环境,这可能最终导致显着改善控制 NS中的白血病进展和NS相关白血病的干细胞移植治疗。

项目成果

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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

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 (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:
    $ 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:
Targeting metabolism in leukemic stem cells
靶向白血病干细胞的代谢
  • 批准号:
    8619417
  • 财政年份:
    2014
  • 资助金额:
    $ 39万
  • 项目类别:

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