JAK2 V617F impairs hematopoietic stem cell function in a conditional knock-in mouse model of JAK2 V617F-positive essential thrombocythemia

Li, Juan, Spensberger, Dominik, Ahn, Jong Sook, Anand, Shubha, Beer, Philip A., Ghevaert, Cedric, Chen, Edwin, Forrai, Ariel, Scott, Linda M., Ferreira, Rita, Campbell, Peter J., Watson, Steve P., Liu, Pentao, Erber, Wendy N., Huntly, Brian J. P., Ottersbach, Katrin and Green, Anthony R. (2010) JAK2 V617F impairs hematopoietic stem cell function in a conditional knock-in mouse model of JAK2 V617F-positive essential thrombocythemia. Blood, 116 9: 1528-1538. doi:10.1182/blood-2009-12-259747


Author Li, Juan
Spensberger, Dominik
Ahn, Jong Sook
Anand, Shubha
Beer, Philip A.
Ghevaert, Cedric
Chen, Edwin
Forrai, Ariel
Scott, Linda M.
Ferreira, Rita
Campbell, Peter J.
Watson, Steve P.
Liu, Pentao
Erber, Wendy N.
Huntly, Brian J. P.
Ottersbach, Katrin
Green, Anthony R.
Title JAK2 V617F impairs hematopoietic stem cell function in a conditional knock-in mouse model of JAK2 V617F-positive essential thrombocythemia
Journal name Blood   Check publisher's open access policy
ISSN 0006-4971
1528-0020
Publication date 2010-09-02
Sub-type Article (original research)
DOI 10.1182/blood-2009-12-259747
Volume 116
Issue 9
Start page 1528
End page 1538
Total pages 11
Place of publication Washington, United States
Publisher American Society of Hematology
Language eng
Formatted abstract
The JAK2 V617F mutation is found in most patients with a myeloproliferative neoplasm and is sufficient to produce a myeloproliferative phenotype in murine retroviral transplantation or transgenic models. However, several lines of evidence suggest that disease phenotype is influenced by the level of mutant JAK2 signaling, and we have therefore generated a conditional knock-in mouse in which a human JAK2 V617F is expressed under the control of the mouse Jak2 locus. Human and murine Jak2 transcripts are expressed at similar levels, and mice develop modest increases in hemoglobin and platelet levels reminiscent of human JAK2 V617F–positive essential thrombocythemia. The phenotype is transplantable and accompanied by increased terminal erythroid and megakaryocyte differentiation together with increased numbers of clonogenic progenitors, including erythropoietin-independent erythroid colonies. Unexpectedly, JAK2V617F mice develop reduced numbers of lineageSca-1+c-Kit+ cells, which exhibit increased DNA damage, reduced apoptosis, and reduced cell cycling. Moreover, competitive bone marrow transplantation studies demonstrated impaired hematopoietic stem cell function in JAK2V617F mice. These results suggest that the chronicity of human myeloproliferative neoplasms may reflect a balance between impaired hematopoietic stem cell function and the accumulation of additional mutations.
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status Non-UQ

Document type: Journal Article
Sub-type: Article (original research)
Collection: UQ Diamantina Institute Publications
 
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