Distinct roles for long-term hematopoietic stem cells and erythroid precursor cells in a murine model of Jak2V617F-mediated polycythemia vera

Mullally, Ann, Poveromo, Luke, Schneider, Rebekka K., Al-Shahrour, Fatima, Lane, Steven W. and Ebert, Benjamin L. (2012) Distinct roles for long-term hematopoietic stem cells and erythroid precursor cells in a murine model of Jak2V617F-mediated polycythemia vera. Blood, 120 1: 166-172. doi:10.1182/blood-2012-01-402396


Author Mullally, Ann
Poveromo, Luke
Schneider, Rebekka K.
Al-Shahrour, Fatima
Lane, Steven W.
Ebert, Benjamin L.
Title Distinct roles for long-term hematopoietic stem cells and erythroid precursor cells in a murine model of Jak2V617F-mediated polycythemia vera
Journal name Blood   Check publisher's open access policy
ISSN 0006-4971
1528-0020
Publication date 2012-07-05
Sub-type Article (original research)
DOI 10.1182/blood-2012-01-402396
Open Access Status Not Open Access
Volume 120
Issue 1
Start page 166
End page 172
Total pages 7
Place of publication Washington, DC, United States
Publisher American Society of Hematology
Language eng
Abstract 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.
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status Non-UQ

Document type: Journal Article
Sub-type: Article (original research)
Collection: School of Medicine Publications
 
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