Study Of The Relationship Between JAK2 Mutant And Polycythemia Vera

Protein tyrosine phosphorylation is controlled by the coordinate action ofprotein tyrosine kinases and protein tyrosine phosphatases, and has a crucialrole in cell proliferation, differentiation, and transformation. Protein tyrosinekinases are the central regulators of signaling pathways. Perturbation of PTKsignaling by mutations and other genetic alterations such as chromosomaltranslocation, interstitial deletion, internal tandem duplication, and amino acidsubstitution results in deregulated kinase activity and malignant transformation.Recently, the mutations of PTKs are correlated with the tumor or cancer inhuman, thus many research groups focus on the relation between PTKs andhuman diseases.Janus kinases (JAKs) are non-receptor protein tyrosine kinases. Inmammals, the family has four members, JAK1, JAK2, JAK3 and TYK2. Theyplay an important role in the cellular signal transduction of cytokine receptorsuperfamily. There are not the tyrosine kinase domain in the cytokine receptor ,so the tyrosine phosphorylation controlled by JAKs is more important. JAK2deficiency results in embryonic lethality at embryonic day 12.5 as a result of afailure in definitive erythropoiesis, so JAK2 has a crucial role in hematopoiesis.JAK-STAT(Signal Transducer and Activators of Transcription ) pathwayhas been extensively studied and the important role has been demonstrated inimmune system regulation, cell proliferation, anti-apoptosis, cell cycleregulation and tumor cell growth. The cell proliferation and differentiation ofhematopoietic cells are controlled by many cytokines including G-CSF, EPO,TPO, IFN and IL. The cytokines combine with their receptors. And then thereceptors are induced the tyrosine phosphorylation by JAK and change thedownstream. JAK-STAT pathway plays an important role in the receptor signaltransduction induced by cytokines in hematopoiesis. The abnormal cellularsignal transduction of JAK-STAT pathway can induce abnormal hematopoiesis.Polycythemia vera (PV) is a clonal myeloproliferative disorder (MPD)characterized by trilineage marrow hyperplasia with increased production of redblood cells, granulocytes, and platelets. PV mostly occurrences in middle andold age population, and are suffered from males more than females. The processof PV is slowly and The main common clinical characteristics of PV isexuberant extramedullary hematopoiesis leading to splenomegaly, spontaneoustransformation to acute leukemia, development of marrow fibrosis at variablerate and, above all, a high risk of thrombotic and hemorrhagic events. Lackingeffective therapeutic tool, the mortality of PV is very high. Therefore the earlydiagnosis of PV is more important.Between March and June 2005, five research groups described a novelJAK2 somatic point mutation (a G-C to T-A transversion, at nucleotide 1849 ofexon 14, resulting in the substitution of valine to phenylalanine at codon 617) inabout 90% PV patients. The findings defined the molecular defection in PV.The JH2 domain can inhibit the activation of JAK2 kinase, and the mutationinduced the decreasing inhibition role and enhancing the activation of kinase. Itwas heterozygous in most patients, so it is an acquired mutation. This discoverybecame the most remarkable fare in the field of haematology 2005, which madepeople focused on JAK2 and the relative diseases.Subsequently, the same mutation was demonstrated in other myeloiddisorders including acute myeloid leukemia, the myelodysplastic syndrome,chronic myelomonocytic leukemia, juvenile myelomonocytic, leukemia,chronic neutrophilic leukemia, hypereosinophilic syndrome, systemicmastocytosis (SM), and other atypical MPD. But the occurrence of mutation isless than PV.In order to define the correlation between JAK2V617F and MPDs, weprepared genomic DNA from a total of 3013 peripheral blood samplesrandomly collected from the blood test laboratory of China Japan UnionHospital, Jilin University. We relied on the allele-specific PCR method toanalyze genomic DNA from blood samples;we found 34 positive samples outof a total of 3013, corresponding to a percentage of 1.1%.To further verify theresults obtained from allele-specific PCR assays, we sequenced PCR positivesamples. Sequencing results confirmed 9 of the samples which contained atleast 7% of the mutant DNA,corresponding to a percentage of 0.3%.Our studythus revealed an unexpectedly high rate of the JAK2V617F mutation in bloods.We can not diagnose any PV patient from the blood test of our collectionwith present diagnosis standard. But the statistics for blood test data of theentire samples displayed the mean of WBC and platelet of JAK2 mutant groupare more than the whole test group, it maybe imply that the JAK2V617F play animportant role in the regulation of hematopoiesis. It maybe has something to dowith the development of myelocyte. We considered that the JAK2V617F mutantis acquired in the early stage of MPDs. It maybe affect other reasons to play animportant role in those diseases.To sum up, there appears important significance for early diagnosis,progonosis and adaptive therapy of PV.