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）是一种以干细胞扩增为特征的克隆干细胞疾病 和成熟血细胞的过度产生，获得性激酶突变 JAK2V617F 在这些过程中发挥着核心作用。 但导致 MPN 干细胞扩增的精确分子机制尚不完全清楚 了解，限制了当前造血异常治疗的有效性。 微环境（利基）开始被认为是发展的重要因素 包括 MPN 在内的血液恶性肿瘤是血液系统的重要组成部分。 造血生态位和大多数造血干细胞位于骨髓窦附近（“血管 与正常骨髓相比，MPN 患者的特点是骨髓血管生成增加 我们最近的工作证明，可以在这些患者中检测到携带 JAK2V617F 突变的 EC。 携带 JAK2V617F 的血管生态位不仅促进 JAK2V617F 突变干细胞的扩增 优先于 JAK2WT 干细胞，但也保护突变细胞免受在 CXCL12（干细胞的重要生态位因子）的水平。 与 JAK2WT EC 相比，携带 JAK2V617F 的 EC 的维持和存活率有所提高。 我们发现血小板生成素 (TPO) 及其受体 MPL（干细胞活性的两个关键调节因子）也与 对于血管生态位功能很重要，MPL 对于 MPN 干细胞的扩增和发育至关重要 携带 JAK2V617F 的血管生态位中骨髓增殖表型的研究 拟议工作的目标。 确定 JAK2V617F 突变改变的生理效应和分子机制 我们特别提出以下建议： 两个具体目标： 目标 1) 检验 JAK2V617F 突变改变血管生态位功能的假设 CXCL12在干细胞移植后促进MPN干细胞扩增和疾病复发的作用。 此外，还将确定 MPN 中携带 JAK2V617F 的血管生态位功能。 将评估 JAK2V617F 突变对人血管内皮功能的影响 目的 2) 检验假设。 JAK2V617F 突变通过改变 TPO/MPL 信号传导改变 MPN 中的血管生态位功能。 该研究计划的长期目标是确定造血系统的分子和细胞功能 正常和肿瘤造血中的血管生态位，并开发更有效的治疗策略 适用于患有 MPN 和潜在其他血液恶性肿瘤的患者。