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

摘要: The JAK2 V617F mutation is found in most patients with a myeloproliferative neoplasm and sufficient to produce phenotype murine retroviral transplantation or transgenic models. However, several lines of evidence suggest that disease influenced by the level mutant signaling, we have therefore generated conditional knock-in mouse which human expressed under control Jak2 locus. Human transcripts are at similar levels, mice develop modest increases hemoglobin platelet levels reminiscent V617F–positive essential thrombocythemia. transplantable accompanied increased terminal erythroid megakaryocyte differentiation together numbers clonogenic progenitors, including erythropoietin-independent colonies. Unexpectedly, JAK2V617F reduced lineage−Sca-1+c-Kit+ cells, exhibit DNA damage, apoptosis, cell cycling. Moreover, competitive bone marrow studies demonstrated impaired hematopoietic stem function mice. These results chronicity neoplasms may reflect balance between accumulation additional mutations.