真性红细胞增多症
造血
骨髓纤维化
生物
干细胞
促红细胞生成素
癌症研究
免疫学
骨髓
发病机制
血小板生成素受体
细胞生物学
内分泌学
血小板生成素
作者
Ann Mullally,Luke Poveromo,Rebekka K. Schneider,Fátima Al‐Shahrour,Steven Lane,Benjamin L. Ebert
出处
期刊:Blood
[American Society of Hematology]
日期:2012-07-05
卷期号:120 (1): 166-172
被引量:66
标识
DOI:10.1182/blood-2012-01-402396
摘要
In the current model of the pathogenesis of polycythemia vera (PV), the JAK2V617F mutation arises in hematopoietic stem cells (HSCs) that maintain the disease, while erythroid precursor populations expand, resulting in excessive red blood cell production. We examined the role of these specific cell populations using a conditional Jak2V617F knockin murine model. We demonstrate that the most immature long-term (LT) HSCs are solely responsible for initiating and maintaining the disease in vivo and that Jak2V617F mutant LT-HSCs dominate hematopoiesis over time. When we induced Jak2V617F expression in erythropoietin receptor expressing precursor cells, the mice developed elevated hematocrit, expanded erythroid precursors, and suppressed erythropoietin levels. However, the disease phenotype was significantly attenuated compared with mice expressing Jak2V617F in LT-HSCs. In addition to developing a PV phenotype, all mice transplanted with Jak2V617F LT-HSCs underwent myelofibrotic transformation over time. These findings recapitulate the development of post-PV myelofibrosis in human myeloproliferative neoplasms. In aggregate, these results demonstrate the distinct roles of LT-HSCs and erythroid precursors in the pathogenesis of PV.
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