Study On The Prevalence Of Protein Tyrosine Kinase JAK2～(V617F) Mutation In The Chinese 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). Infrequent occurrence of this mutation has been also reported in chronic myelomo—nocytic leukemia (CMML) , atypical myeloproliferative disorders (MPDs), myelodysplastic syndrome (MDS) , systemic mastocytosis (SM) , chronic neutrophilic leukemia (CNL) , and acute myeloid leukemia (AMD .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 transplantation 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.In order to further study on the prevalence of JAK2^V617F mutation in Chinese population, at first we set up a method called allele-specific PCR, to detect the mutation in genomic DNA from blood samples. This method could detect not low than 0.1% mutation rate. The sensitivity of ASP is higher than the traditionary DNA sequencing.In a long period of time, we continuous and randomly selected 1971 donors' peripheral blood in all: Group1 is healthy donors who had no disease at all; Group 2 is hematologic disease patients group; Group 3 is patients with other diseases except hematologic disease. The result shows that there is no JAK2^V617F mutatiaon in Group 1 at all, while the prevalence of Group 2 is 5.56%, and of Group 3 is 0.84%. The date suggests that this mutation be apparently much more common than MPDs. Its occunence may be a prelude to full blood cell abnormalities and other diseases, but it cannot by itself diagnose MPDs.From the blood test results of three groups, the JAK2^V617F positive samples in Group 2 often had elevated red cell, platelet counts and hemoglobin level, but the white cell counts didn't change. The blood test results of JAK2^V617F positive samples in Group 3 showed no differences from the entire Group 3. It indicated that JAK2^V617F mutation might intensify hematological system disorder of the patients with hematopathy, comparing with other patients whose hematological system was not affected.From the relationship between JAK2^V617F mutation and diseases, there were 9 cases of JAK2^V617F mutation in the group of hemopathic patients containing only one non-MPD patient, and it belonged to M₂b subtype of ANLL M₂ differentiated type. It hasn't been reported that there is JAK2^V617F mutation in this desease.There were 8 cases of JAK2^V617F mutation in the group of non-hemopathic patients containing cancer diseases (one case of esophageal cancer, two cases of lung cancer), cerebrovascular diseases (one case of cerebral circulation insufficiency, one case of cerbral infarction), and nervous system disease (one case of Parkinson's disease) which might be due to basal ganglia lesions result from cerebrovascular disease. And there was one case of early pregnancy without conclusive diagnosis, which needed a further study. In addition, there was no JAK2^V617F mutation in some common diseases containing heart diseases, urinary system diseases, immune system diseases, diabetes, cirrhosis and pneumonia. It indicated that JAK2^V617F mutation might exert a potential role in tumorigeness and cerebrovascular diseases.Our data demonstrate that the mutation is much more common than MPDs and is present in patients with many other conditions that have not manifested MPDs. Considering its greatly enhanced kinase activity, the mutant JAK2 should have pathogenic implications. JAK2^V617F may not be used exclusively for the diagnosis of MPDs, but it may be useful for the early identification 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 JAK2V617F mutation further suggests its importance to human health. Therefore, further studies to define its pathologic role and the correlation of its occurrence with environmental factors are warranted. Surveying a large series of patients will precisely define the occurrence and role of this mutation in the different diseases, whereas further development of animal models will be useful in the development of new, targeted therapeutic approaches in these pathologies.