Study On The Prevalence Of Protein Tyrosine Kinase JAK2V617F Mutation In The Western Population

Protein tyrosine kinases are central regulators of signaling pathways and are attractive therapeutic targets. Perturbation of PTK signaling by mutations and other genetic alterations such as chromosomal translocation, interstitial deletion, internal tandem duplication, and amino acid substitution results in deregulated kinase activity and malignant transformation.JAK2 is a tyrosine kinase involved in signaling pathways regulating cell growth. In 2005, several groups identified a recurrent somatic activating mutation in the JAK2 tyrosine kinase in polycythemia vera (PV), essential thrombocythemia (ET), and idiopathic myelofibrosis(IMF). Subsequent studies revealed infrequent occurrence of this mutation chronic myelomo-nocytic leukemia(CMML), atypical myeloproliferative disorders (MPDs), myelodysplastic syndrome(MDS), systemic mastocytosis(SM), chronic neutrophilic leukemia(CNL), and acute myeloid leukemia(AML).This mutation results in a valine to phenylalanine substitution within the pseudokinase domain of JAK2, which is involved in the auto-inhibition of its tyrosine kinase activity. The mutant JAK2 possesses enhanced tyrosine kinase activity and causes a PV-like phenotype in mouse bone marrow transplant and transgenic models. However, it remains unclear whether the JAK2^V617F mutation is solely responsible for these diseases and why it is associated with such a wide spectrum of phenotypes.Interestingly, our recent study also demonstrated that near 1% of blood samples collected from a Chinese hospital population bear the JAK2^V617F mutation. Most of these JAK2^V617F positive patients do not meet the criteria for diagnosis of MPDs but developed vascular diseases including thrombosis, coronary heart disease, arteriosclerosis, cerebral ischemia, and cerebral infarction. These data imply that JAK2^V617F mutation is much more common than MPDs and may represent a pre-MDPs condition with other pathological consequences. In order to study further the prevalence of JAK2^V617F mutation in non MPD patients, we analyze samples collected from Western population. We used a method, named allele-specific PCR, to detect the mutation in genomic DNA from blood cell and bone marrow cell of patients. This method could detect up to 0.1% mutation rate. The sensitivity of ASP is much higher than the conventional DNA sequencing which has a limit of 5%.In this study, we analyzed 2138 peripheral blood and bone marrow samples collected in a cytogenetic laboratory over a long period of time. The samples are divined into two groups. Group 1 is non-hematologic disease patients (mainly for screening of genetic diseases); group 2 is hematologic disease patients. The results demonstrated that there is no JAK2^V617F mutation in group1, while 4.86% of group 2 has the mutation. Among the 24 JAK2^V617F-positive samples in group 2, 11 are from MPD patients, and 13 are from non-MPD patients including anemia (how many?), leukemia (how many?), MDS (how many?) patients, and lymphoma (3 cases). It should be pointed out that occurrence of JAK2^V617F in lymphoma has never been reported.Our data suggest that the mutation is much more common than MPDs and is primarily related to patients with hematological disorders. JAK2^V617F may not be used exclusively for the diagnosis of MPDs, but it may be useful for the early diagnosis of MPDs and other diseases, for the prognosis of these diseases, and for designing proper prevention and treatment methods. The relatively high incidence of the JAK2^V617F mutation further suggests its importance to human health. It is common to both Eastern and Western populations. Therefore, further studies to define its pathologic role and the correlation of its occurrence with environmental factors are necessary. In addition, surveying a broader range of patients many help to define the implication of JAK2^V617F mutation in other blood-related diseases. Finally, further development of animal models will be useful in the development of new, targeted therapeutic approaches in these pathologies.