Proceedings of the International scientific and practical conference ―Science at the Frontier of Progress‖ (June 8-10, 2026) / Publisher website: www.naukainfo.com. – Paris, France, 2026. - 178 p.

24 suppressors of cytokine signaling (SOCS) and protein inhibitors of activated STATs (transcriptional repressors of PIAS). JAK2, and possibly other JAK kinase family proteins, are also involved in the expression of the related receptors EPO-R and TPO-R on the cell surface, acting as a chaperone and protein stabilizer. The mechanism of JAK/STAT signaling is relatively simple. However, the biological consequences of the pathway are complicated by its cross-talk with other signaling pathways [9, 13]. To date, there is no clear explanation for the development of different nosological forms of CMPN when the same JAK/STAT signaling cascade is activated. One of the key points in the pathogenesis of the entire group of diseases not associated with BCR- ABL is often the occurrence of a mutation in the JAK2 gene. The JAK2 V617F mutant protein exerts its effect in the bone marrow on hematopoietic stem cells and causes mutation in several autonomous hematological lineages. The mutated JAK2 protein was detected in myeloid cells, bone marrow cells, granulocytes, platelets and erythroblasts, but not in T lymphocytes. Also, the mutation was not found in non- hematopoietic cells. Thus, depending on the nature of the JAK2 V617F positive stem cells, the patient may develop either IP, ET or PMF. It is likely that some currently unknown factors may modulate the activity of mutant JAK2. However, it is not known whether the mutant protein requires receptor binding or spontaneously oligomerizes on the membrane or in the cytoplasm of the cell to activate the signaling cascade [5]. There is a hypothesis that the gradual accumulation of the JAK2 V617F mutation (increasing allelic load) causes the transition from one CMPN to another. At a low level of the mutant allele (the bulk of cells are heterozygous for JAK2 V617F), ET develops; as the number of mutated cells, including homozygous for it, increases, IP develops, and then PMF. The results obtained formed the basis of the genetic hypothesis of the ―dose-response‖ development of CMPN: a different phenotype of the nosological variant of this group of diseases: IP, PMF or ET is determined by a different degree of JAK2 V617F allelic load and, as a result, different activation of the JAK/STAT signaling pathway. Low allelic burden associated with worse survival in PMF, V617F-negative cell clone gives this disease a more aggressive phenotype. Somatic mutations in exon 12 of the JAK2 gene are highly specific for IP, but are found in only 4– 5% of patients with this disease and are not found in ET and PMF. Mutations in exon 12 or 14 of the JAK2 gene lead to independent activation of the JAK/STAT signaling system by modifying the structure and function of the JAK2 protein. Activation of JAK kinase occurs independently of the binding of erythropoietin to its receptor. This protein constantly transmits a signal to the nucleus and cells continuously divide, i.e. their increased proliferation is observed. Thus, the JAK/STAT pathway cascade provides a direct mechanism for translating an extracellular signal into a transcriptional response. Data on the diagnostic significance of somatic mutations in the CALR gene have allowed us to prove the clonal nature of the disease in JAK2 V617F-negative patients. Calreticulin is a multifunctional regulatory protein located in the endoplasmic reticulum. Its function is to maintain calcium homeostasis and protein quality, it is also involved in the signal transduction process in the JAK/STAT pathway. About 36 types of different mutations of the CALR gene (mainly in exon 9) have been described, leading to increased activation of the signaling pathway and, as a result, increased proliferation of megakaryocytes. All mutations of the CALR gene lead to a shift in the reading frame and a change in the C-terminal sequence of the calreticulin protein [5]. Molecular analysis has revealed that approximately 3% of ET patients also have other somatic mutations, for example, in codon 515 of the MPL gene, located in the cytoplasmic juxtamembrane region: W515L (substitution of tryptophan for leucine) and W515K (substitution of tryptophan for lysine). Transformation of ET into IP was observed only in patients with the JAK2 V617F mutation. The best survival and the lowest risk of thrombosis were in patients with CALR mutations. The worst prognosis was observed in patients without clonal markers (JAK2V617F, MPL and CALR mutations), the so-called triple negative cases of ET [5]. In IP, ET and PMF, mutations in the TET2, IDH1/IDH2, EZH2, LNK, CBL, ASXL1, IKZF1 genes can also be detected. These changes lead to activation of the JAK/STAT signaling pathway and increased proliferation of the myeloid sprout. Mutations in the TET2, ASXL1, EZH2 genes probably introduce epigenetic disorders in the regulation of transcription. It is clear that in CMPN, the JAK/STAT signaling system becomes dysregulated (overactive), resulting in excessive proliferation of hematopoietic stem cells and excessive stimulation of inflammatory processes. The discovery of this feature led to the development of JAK inhibitors, in particular, Ruxolitinib, the first oral selective JAK1 and JAK2 inhibitor approved for use in patients with intermediate and high risk of PMF and patients with IP who are intolerant to or resistant to hydroxycarbamide. Ruxolitinib inhibits