Identification of Therapeutic Targets in the Hematopoietic Vascular Niche

造血血管生态位中治疗靶点的识别

• 批准号: 10043821
• 负责人: Huichun Zhan
• 金额: --
• 依托单位: NORTHPORT VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-10-01 至 2023-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10043821
• 关键词: Affect; Alleles; Blood Cells; Blood Vessels; Bone Marrow Transplantation; CD34 gene; CD34+CD38- cell; CXCL12 gene; Cell Line; Cell Maintenance; Cell Survival; Cell physiology; Cells; Chemotherapy and/or radiation; Clinical; Coculture Techniques; Development; Discontinuous Capillary; Disease; Effectiveness; Endothelial Cells; Exposure to; Genetic; Goals; Hematologic Neoplasms; Hematopoiesis; Hematopoietic; Hematopoietic stem cells; Human; Immunofluorescence Immunologic; In Vitro; Knockout Mice; Knowledge; Magnetic Resonance Imaging; Marrow; Methods; Military Personnel; Molecular; Morbidity - disease rate; Mus; Mutation; Myeloproliferative disease; Patients; Phenotype; Phosphotransferases; Physiological; Play; Population; Recurrent disease; Research Proposals; Resistance; Risk; Role; Signal Transduction; Stains; Stem Cell Factor; Stem cell transplant; Stromal Cell-Derived Factor 1; Structure; System; Technology; Testing; Thrombopoietin; Toxic Environmental Substances; Transgenic Organisms; Underserved Population; Vascular Endothelial Cell; Vascular Endothelium; Veterans; Work; angiogenesis; conditioning; contrast enhanced; human disease; in vivo; induced pluripotent stem cell; inhibitor/antagonist; irradiation; knockout gene; mortality; mouse model; mutant; neoplastic; novel; peripheral blood; preference; receptor; small hairpin RNA; stem cell expansion; stem cell function; stem cell proliferation; stem cells; therapeutic target; therapeutically effective

The myeloproliferative neoplasms (MPNs) are clonal stem cell disorders characterized by stem cell expansion and overproduction of mature blood cells. The acquired kinase mutation JAK2V617F plays a central role in these disorders, but the precise molecular mechanisms responsible for MPN stem cell expansion are not fully understood, limiting the effectiveness of current treatments. Abnormalities of the hematopoietic microenvironment (niche) are beginning to be recognized as an important factor in the development of hematologic malignancies including MPNs. Endothelial cells (ECs) are an essential component of the hematopoietic niche and most hematopoietic stem cells reside adjacent to a marrow sinusoid (the “vascular niche”). Patients with MPNs are characterized by increased marrow angiogenesis compared to normal marrow and ECs carrying the JAK2V617F mutation can be detected in these patients. Our recent work demonstrated that the JAK2V617F-bearing vascular niche not only promotes the expansion of JAK2V617F-mutant stem cells in preference to JAK2WT stem cells but also protects the mutant cells from lethal irradiation administered during conditioning for marrow transplantation. The levels of CXCL12, an essential niche factor for stem cell maintenance and survival, are increased in JAK2V617F-bearing ECs compared to JAK2WT ECs. In addition, we found that thrombopoietin (TPO) and its receptor MPL, two key regulators of stem cell activity, are also important for the vascular niche function and MPL is essential for MPN stem cell expansion and the development of myeloproliferative phenotype in the JAK2V617F-bearing vascular niche. The objective of the proposed work is to determine the physiological effects and the molecular mechanisms by which the JAK2V617F mutation alters the hematopoietic vascular niche to promote MPN stem cell expansion. In particular, we propose the following two specific aims: Aim 1) To test the hypothesis that the JAK2V617F mutation alters vascular niche function to promote MPN stem cell expansion and disease relapse after stem cell transplantation. The roles of CXCL12 in JAK2V617F-bearing vascular niche function in MPNs will be determined. In addition, the effects of the JAK2V617F mutation on human vascular endothelium function will be assessed. Aim 2) To test the hypothesis that the JAK2V617F mutation changes vascular niche function in MPNs via altered TPO/MPL signaling. The long term goal of this research proposal is to define the molecular and cellular functions of the hematopoietic vascular niche in both normal and neoplastic hematopoiesis, and to develop more effective therapeutic strategies for patients with MPNs and potentially other hematologic malignancies.

骨髓增生性肿瘤（MPN）是以干细胞膨胀为特征的克隆干细胞疾病 成熟血细胞过量生产。获得的激酶突变JAK2V617F在这些中起着核心作用 疾病，但是负责MPN干细胞扩展的精确分子机制并非完全 理解，限制当前治疗的有效性。造血异常 微环境（利基）开始被认为是发展的重要因素 血液系统恶性肿瘤在内，包括MPN。内皮细胞（EC）是 造血生态位和大多数造血干细胞居住在骨髓正弦（“血管） ）。与正常骨髓相比，MPN的患者的特征是骨髓血管生成增加 在这些患者中可以检测到携带JAK2V617F突变的EC。我们最近的工作证明了 含有JAK2V617F的含有含有JAK2V617F突变干细胞的膨胀 优先于JAK2WT干细胞，但也可以保护突变细胞免受致命辐射的影响。 骨髓移植的条件。 CXCL12的水平，干细胞的基本生态位因子 与JAK2WT EC相比，JAK2V617F EC的维持和生存率增加。此外， 我们发现，血小板蛋白（TPO）及其接收器MPL是干细胞活性的两个关键调节剂，也是 对于血管生态位功能和MPL的重要 含有JAK2V617F的含有髓增生性表型的表型。拟议工作的目的 是确定JAK2V617F突变改变的物理效应和分子机制 造血血管生态裂促进MPN干细胞膨胀。特别是，我们提出以下内容 两个具体的目的：目标1）测试JAK2V617F突变将血管生态裂函数的假设变为 在干细胞移植后促进MPN干细胞扩张和疾病缓解。 CXCL12在 将确定MPN中含有JAK2V617F的含有含有的血管生态位功能。另外， 将评估对人血管内皮功能的JAK2V617F突变。目标2）检验假设 JAK2V617F突变通过改变的TPO/MPL信号传导改变了MPN中的血管小众功能。这 该研究建议的长期目标是定义造血的分子和细胞功能 正常和肿瘤造血的血管生态市场，并制定更有效的治疗策略 适用于MPN和可能其他血液学恶性肿瘤的患者。