Physiology and genetics
JAK is tyrosine kinases, phosphorylating STAT factors (Janus kinase – named because of the presence of two kinase domains in one molecule) are associated with cytokine receptors but are inactive until the receptors aggregate under the action of cytokines (similar to growth factor receptors). After aggregation, JAK is activated by transphosphorylation. Activated JAK phosphorylates many tyrosines in the cytoplasmic receptor. Protein molecules, commonly known as STAT (signal transducers and activators of transcription) proteins, are attached to these phosphotyrosines. STAT proteins dimerize and penetrate the nucleus. There, they induce the transcription of certain genes.
Myeloproliferative diseases (MPD) are diseases characterized by excessive proliferation (production of cells) of one or more germs of hematopoiesis. Violations occur at the level of stem cells, as a result of which erythremia, subleukemic myelosis, thrombocythemia and chronic myelogenous leukemia can develop.
Indications for analysis
- Establishing or confirming a diagnosis of true polycythemia, essential thrombocythemia, or idiopathic myelofibrosis;
- Differential diagnosis of true polycythemia and secondary erythrocytosis;
- Differential diagnosis of essential thrombocythemia and reactive thrombocytosis;
- Determining the risk of thrombosis;
- Determining the risk of abortion;
- Additional differential diagnosis of idiopathic myelofibrosis and atypical forms of MPZ;
- Addition to the cytogenetic and histological examination of the bone marrow.
Recent studies have found a connection between the V617F mutation in the JAK2 gene and classical bcr / abl-negative MPDs: true polycythemia (Wakez’s disease), essential thrombocythemia (ET), and idiopathic myelofibrosis (MI). In addition, this mutation in rare cases occurs with atypical MPZ and myelodysplastic syndromes.
The somatic mutation V617F leads to an increase in the signal from JAK2, leading to excessive proliferation of a particular cell germ. In a study by E Joanna Baxter et al.  has been shown that the V617F mutation occurs in 97% of true polycythemia, 57% of essential thrombocythemia, and 50% of idiopathic myelofibrosis.
The results are consistent with studies by other groups of authors: 65-97% with true polycythemia, 23-57% with essential thrombocythemia, and 35-95% with idiopathic myelofibrosis.
Peter J Campbell et al.  analyzed the relationship of V617F polymorphism with various blood counts in patients with essential thrombocythemia. 806 patients took part in the work. The authors noted an increase in hemoglobin level (on average by 9.6 g / l; 95% CI, 7.6–11.6 g / l; P = 0.0001) and neutrophils (by 1.1×109 / l; 95% CI, 0.7–1.5×109 / l; P = 0.0001), as well as a decrease in serum erythropoietin (by 13.8 U / L; 95% CI, 10.8–16.9 U / L; P = 0.0001) and ferritin (n = 182; 58 vs. 91 g / L; P = 0.01) patients with the studied polymorphism.
Myeloproliferative diseases contribute to the development of venous thrombosis. So, Colaizzo D. et al.  analyzed case histories of 99 patients with portal (portal) vein thrombosis (TBV) and mesenteric vessel thrombosis. A mutation of the JAK2 V617F gene was found in 17 people (17.2%). None of these patients showed congenital risk factors for thrombophilia. 7 out of 17 patients with a JAK2 V617F mutation (43.8%) and another 2 people (2.4%) without a JAK2 V617F mutation at the time of the first episode of venous thrombosis were diagnosed with MPZ. During the follow-up period, which averaged 41 months, 3 more patients with JAK2 V617F mutation showed myeloproliferative processes. Scientists came to the conclusion that the studied polymorphism is a marker of venous thrombosis, and is also necessary for a more thorough examination of patients for the development of myeloproliferative diseases.
An interesting observation was presented by Stefano et al.  They determined the mutation in the JAK2 V617F gene in 139 adult patients (over 18 years old) with or without chronic MPD with hepatic vein thrombosis (15 people), extrahepatic TBB and / or mesenteric veins (79 people) and cerebral veins (45 people) ) Only 19 patients fully met the criteria for true polycythemia (8 people) or essential thrombocythemia (11 people) at the time of thrombosis: 4 patients developed hepatic vein thrombosis, 11 – TBB and / or mesenteric vein thrombosis, 4 patients – cerebral vein thrombosis. Mutation in the JAK2 V617F gene was detected in 94.7% of patients with chronic MPZ, in 21.5% of patients with abdominal vascular thrombosis without MPZ, and in 4.8% of patients with cerebral vein thrombosis without MPZ. Among patients without MCH and without thrombophilia, but with unprovoked thrombosis, 29.4% had vein thrombosis of the internal organs, 42.8% had TBB – simultaneously with the presence of the JAK2 V617F gene mutation. Thus, even in the absence of signs of obvious MPD, a significant proportion of patients with TBV and cerebral thrombosis carry the JAK2 V617F mutation and have a high risk of recurring thrombosis.
Mercier et al. (2007)  investigated the presence of the JAK2 gene V617F mutation in 3496 women due to the risk of miscarriage. Researchers found that somatic mutation is largely associated with fetal loss (OR = 4.63; P = 0.002) and embryonic loss (OR = 7.20; P = 0.009). The authors note that the risk of miscarriage in the studied women in the presence of a mutation increased regardless of the genotypes of 1691A Lyayden factor and 20210A prothrombin.
Important Note: V617F mutation is somatic, i.e.:
- Occurs in a person spontaneously, and is not inherited from parents;
- The mutant allele is detected mainly in the form of a heterozygous genotype;
- A mutation may occur several years after this analysis, therefore, if necessary, reanalysis is advisable.
Known JAK 2 inhibitors are AC430, SB1578, and CEP-33779.