Biopharmaceutical R&D Center, Chinese Academy of Medical Sciences, Peking Union Medical College, Suzhou, People's Republic of China.
Department of Medicine, Division of Hematology-Oncology, Stony Brook Medicine, Stony Brook, New York, USA.
Stem Cells. 2018 Nov;36(11):1676-1684. doi: 10.1002/stem.2888. Epub 2018 Jul 29.
The myeloproliferative neoplasms (MPNs) are stem cell disorders characterized by hematopoietic stem/progenitor cell (HSPC) expansion and overproduction of mature blood cells. The acquired kinase mutation JAK2V617F plays a central role in these disorders. The mechanisms responsible for HSPC expansion in MPNs are not fully understood, limiting the effectiveness of current treatments. One hallmark feature of the marrow in patients with MPNs is megakaryocyte (MK) hyperplasia. Previously, we reported that JAK2V617F-bearing MKs cause a murine myeloproliferative syndrome with HSPC expansion. Here we show that JAK2V617F MKs promote MPN stem cell function by inducing HSPC quiescence with increased repopulating capacity. In addition, we demonstrate that thrombopoietin and its receptor MPL are critical for the JAK2V617F-bearing MK-induced myeloproliferation, both by directly affecting the quantity and quality of MKs and by altering the MK-endothelial interaction and vascular niche function. Therefore, targeting HSPC niche-forming MKs and/or their interactions within the vascular niche could provide novel, more effective therapeutic strategies in patients with MPNs. Stem Cells 2018;36:1676-1684.
骨髓增殖性肿瘤（MPN）是一种造血干细胞/祖细胞（HSPC）过度扩张和成熟血细胞过度生成的干细胞疾病。获得性激酶突变 JAK2V617F 在这些疾病中起着核心作用。导致 MPN 中 HSPC 扩张的机制尚未完全阐明，这限制了当前治疗方法的有效性。MPN 患者骨髓的一个显著特征是巨核细胞（MK）增生。此前，我们报道了携带 JAK2V617F 的 MK 导致具有 HSPC 扩张的小鼠骨髓增殖性综合征。在这里，我们表明 JAK2V617F MK 通过增加自我更新能力诱导 HSPC 静止来促进 MPN 干细胞功能。此外，我们证明血小板生成素及其受体 MPL 通过直接影响 MK 的数量和质量以及改变 MK-内皮相互作用和血管龛功能，对携带 JAK2V617F 的 MK 诱导的骨髓增殖是至关重要的。因此，针对 HSPC 龛形成 MK 及其在血管龛内的相互作用可能为 MPN 患者提供新的、更有效的治疗策略。干细胞 2018；36:1676-1684。
