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
• 负责人: CHENG-KUI QU
• 金额: $ 42.23万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 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: https://reporter.nih.gov/project-details/10208202
• 关键词: Adrenergic Receptor; Blood; Bone Marrow; Bone Marrow Cells; Cell surface; Cells; Clinical Management; Data; Development; Disease; Embryonic Development; Face; Funding; Genes; Germ-Line Mutation; Hematologic Neoplasms; Hematopoietic; Hematopoietic stem cells; Hormones; Human; In Vitro; Juvenile Myelomonocytic Leukemia; Knock-in Mouse; Knowledge; Laboratories; Lead; Maintenance; Malignant Childhood Neoplasm; Malignant Neoplasms; Mediating; Mental Retardation; Mesenchymal Stem Cells; Molecular; Mus; Mutate; Mutation; Myeloproliferative disease; Nerve Fibers; Neural Crest; Neuroglia; Neurotransmitters; Noonan Syndrome; Osteoblasts; PTPN11 gene; Pathogenesis; Pathogenicity; Patients; Peripheral Nervous System; Prevention; Prognosis; Protein Tyrosine Phosphatase; Proteins; Ras Signaling Pathway; Receptor Signaling; Research; Risk; Role; Schwann Cells; Signal Pathway; Signaling Molecule; Specimen; Stem cell transplant; Structure; Testing; Therapeutic Intervention; Transplantation; Treatment outcome; Work; cell type; chemokine; congenital heart disorder; cytokine; design; developmental disease; gain of function; improved; leukemia; leukemogenesis; mouse model; mutant; nerve stem cell; nestin protein; novel; novel therapeutic intervention; novel therapeutics; osteoprogenitor cell; prevent; stem cells; therapeutic development; trafficking; transplantation therapy

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 Noonan综合征（NS），一种以先天性心脏病，营养不良为特征的发育障碍 面部结构，身材矮小和智力低下是由所涉及的基因种系突变引起的 在RAS信号通路中。 NS患者患白血病的风险增加。这 白血病发生的机制尚不完全了解。 NS主要（> 50％）相关 蛋白质酪氨酸磷酸酶PTPN11（SHP2）中的生殖线杂合激活突变和NS PTPN11突变患者的预后最差。我们实验室和其他人的研究 确定了造血细胞内在PTPN11突变在NS-发病机理中的因果作用 相关的白血病。值得注意的是，在最后的资金期间，我们发现PTPN11激活突变 （E76K或D61G）在骨髓（BM）基质中，特别是表达巢穴和表达巢的细胞 衍生的间充质干细胞和破骨剂，对发育有显着贡献/ 小鼠模型中血液学恶性肿瘤的进展。但是，我们对 BM微环境中的PTPN11疾病突变仍然不完整。我们最近的飞行员数据表明 PTPN11激活周围神经系统（PNS）和其他神经rest衍生的进展 在BM基质中，还对居民施加不利影响HSC神经特异性PTPN11E76K突变 敲入小鼠（PTPN11E76K/+/WNT1-CRE+）开发了骨髓增生性肿瘤（MPN），并且这种恶性肿瘤 起源于野生型造血干细胞（HSC）。此外，供体细胞衍生的MPN（D-MPN） 在PTPN11E76K/+/WNT1-CRE+小鼠中开发，该小鼠用健康的BM细胞移植。总体目标 应用是破译神经元中PTPN11突变的细胞和分子机制 BM基质中的波峰衍生的细胞诱导MPN。该提案的中心假设是PTPN11 这些微环境细胞中的突变通过直接和/或间接驱动白血病发育 过度激活的居民HSC。我们计划检验这一假设并实现此应用的目标 通过追求以下三个目标。 1）。确定细胞类型，蛋白质因子和/或神经递质 介导PNS和其他神经rest衍生物中PTPN11激活突变的白血病作用 在BM基质中。 2）。确定PTPN11功能获得激活的分子机制 突变放大了PNS和其他神经rest衍生的细胞的活性。 3）。验证 NS患者标本和 患者衍生的细胞。本应用程序中提出的研究不仅会大大提高我们的理解 NS中白血病的基础机制，但也为新的理性设计提供了信息 预防NS中白血病发展和改善干细胞移植的治疗干预措施 与NS相关血液系统恶性肿的治疗。