Journal
BLOOD
Volume 116, Issue 9, Pages 1528-1538Publisher
AMER SOC HEMATOLOGY
DOI: 10.1182/blood-2009-12-259747
Keywords
-
Categories
Funding
- Leukemia Research Fund
- Wellcome Trust
- Medical Research Council
- British Heart Foundation
- Kay Kendall Leukaemia Fund
- Cambridge NIHR Biomedical Research Center
- Leukemia & Lymphoma Society of America
- British Heart Foundation [FS09039]
- MRC [G116/187, G0800784] Funding Source: UKRI
- British Heart Foundation [FS/09/039/27788] Funding Source: researchfish
- Medical Research Council [G0800784, G0800784B, G116/187, G0300723B] Funding Source: researchfish
Ask authors/readers for more resources
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, JAK2(V617F) 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 JAK2(V617F) 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. (Blood. 2010;116(9):1528-1538)
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available