Loss of wild-type Jak2 allele enhances myeloid cell expansion and accelerates myelofibrosis in Jak2V617F knock-in mice

Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, U.K (Impact Factor: 10.43). 01/2014; 28(8). DOI: 10.1038/leu.2014.52
Source: PubMed


JAK2V617F is the most common mutation found in Philadelphia chromosome-negative myeloproliferative neoplasms (MPNs). Although a majority of MPN patients carry heterozygous JAK2V617F mutation, loss of heterozygosity (LOH) on chromosome 9p involving the JAK2 locus has been observed in ~30% of MPN patients. JAK2V617F homozygosity via 9pLOH has been associated with more severe MPN phenotype. However, the contribution of 9pLOH in the pathogenesis of MPNs remains unclear. To investigate the roles of wild-type JAK2 (JAK2 WT) and JAK2V617F alleles in the development of MPNs, we have utilized conditional Jak2 knock-out and Jak2V617F knock-in mice and generated heterozygous, hemizygous and homozygous Jak2V617F mice. Whereas heterozygous Jak2V617F expression results in a polycythemia vera-like MPN in mice, loss of Jak2 WT allele in hemizygous or homozygous Jak2V617F mice results in markedly increased white blood cells, neutrophils, reticulocytes and platelets in the peripheral blood, and significantly larger spleen size compared with heterozygous Jak2V617F mice. Hemizygous or homozygous Jak2V617F mice also exhibit accelerated myelofibrosis compared with mice expressing heterozygous Jak2V617F. Together, these results suggest that loss of Jak2 WT allele increases the severity of the MPN. Thus, the Jak2 WT allele functions as a negative regulator of MPN induced by Jak2V617F.Leukemia accepted article preview online, 31 January 2014. doi:10.1038/leu.2014.52.

25 Reads
  • [Show abstract] [Hide abstract]
    ABSTRACT: Dameshek first postulated a common myeloproliferative heritage for the myeloproliferative disorders, now termed neoplasms. This prescient observation was validated by the description of a common mutation in exon 14 of JAK2 for patients with essential thrombocythemia, polycythemia vera and primary myelofibrosis. In recent years, our knowledge of the molecular abnormalities underpinning these disorders has expanded significantly. At the same time, we have continued to use a classification based largely upon the first clinical descriptions of these entities, which sometimes proves problematic in differentiating between these conditions and normal reactive processes, myelodysplasia and between the myeloproliferative neoplasm entities themselves. Here, we discuss the pros and cons of a molecular classification and its potential utility in diagnosis, prognosis, and therapeutics.
    Current Hematologic Malignancy Reports 10/2013; 8(4). DOI:10.1007/s11899-013-0179-9 · 2.20 Impact Factor

Preview (2 Sources)

25 Reads
Available from