Identification of Therapeutic Targets in the Hematopoietic Vascular Niche

骨髓增生性肿瘤（MPN）是以干细胞扩增为特征的克隆性干细胞疾病 以及成熟血细胞的过度生成。获得性激酶突变JAK 2 V617 F在这些疾病中起着核心作用。 疾病，但负责MPN干细胞扩增的精确分子机制还不完全清楚。 这限制了目前治疗的有效性。造血功能障碍 微环境（生态位）开始被认为是发展的重要因素， 血液恶性肿瘤，包括MPN。内皮细胞（EC）是血管内皮细胞的重要组成部分。 造血小生境和大多数造血干细胞位于骨髓窦（“血管窦”）附近 niche”）。与正常骨髓相比，MPN患者的特点是骨髓血管生成增加 在这些患者中可以检测到携带JAK 2 V617 F突变的EC。我们最近的研究表明 携带JAK 2 V617 F的血管小生境不仅促进JAK 2 V617 F突变干细胞的扩增， 但也保护突变细胞免受在治疗期间施用的致死辐射。 准备骨髓移植。CXCL 12是干细胞的一个重要的生态位因子， 与JAK 2 WT EC相比，携带JAK 2 V617 F的EC中的维持和存活增加。此外，本发明还提供了一种方法， 我们发现，血小板生成素（TPO）及其受体MPL是干细胞活性的两个关键调节因子， MPL对血管生态位功能很重要，MPL对MPN干细胞扩增和发育至关重要。 在JAK 2 V617 F-承载血管生态位中的骨髓增殖表型。拟议工作的目标 是确定JAK 2 V617 F突变改变的生理效应和分子机制。 造血血管龛促进MPN干细胞扩增。我们特别提出以下建议： 两个具体目的：目的1）检验JAK 2 V617 F突变改变血管生态位功能的假设， 促进MPN干细胞扩增和干细胞移植后疾病复发。CXCL 12在 将确定MPN中携带JAK 2 V617 F的血管生态位功能。此外， 将评估JAK 2 V617 F突变对人血管内皮功能的影响。（2）检验假设 JAK 2 V617 F突变通过改变TPO/MPL信号传导改变了MPN中的血管生态位功能。的 这项研究计划的长期目标是确定造血干细胞的分子和细胞功能， 血管生态位在正常和肿瘤造血，并制定更有效的治疗策略 用于MPN和潜在的其他血液恶性肿瘤患者。

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.