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

Li, J., Spensberger, D., Ahn, J.S., Anand, S., Beer, P.A., Ghevaert, C., Chen, E., Forrai, A., Scott, L.M., Ferreira, R., Campbell, P.J., Watson, S.P., Liu, P., Erber, W.N., Huntly, B.J., Ottersbach, K. and Green, A.R. 2010. JAK2 V617F impairs hematopoietic stem cell function in a conditional knock-in mouse model of JAK2 V617F-positive essential thrombocythemia. Blood. 116, pp. 1528-1538. https://doi.org/10.1182/blood-2009-12-259747

TitleJAK2 V617F impairs hematopoietic stem cell function in a conditional knock-in mouse model of JAK2 V617F-positive essential thrombocythemia
TypeJournal article
AuthorsLi, J., Spensberger, D., Ahn, J.S., Anand, S., Beer, P.A., Ghevaert, C., Chen, E., Forrai, A., Scott, L.M., Ferreira, R., Campbell, P.J., Watson, S.P., Liu, P., Erber, W.N., Huntly, B.J., Ottersbach, K. and Green, A.R.
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 lineage−Sca-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.

JournalBlood
Journal citation116, pp. 1528-1538
ISSN0006-4971
Year2010
PublisherAmerican Society of Hematology
Digital Object Identifier (DOI)https://doi.org/10.1182/blood-2009-12-259747
Publication dates
Published02 Sep 2010

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