Proceedings of the International scientific and practical conference ―Science at the Frontier of Civilizations‖ (March 16-18, 2026) / Publisher website: www.naukainfo.com. – Helsinki, Finland, 2026. - 145 p.

7 With the increasing availability of genetic sequencing in research and now in routine diagnostic settings, the genetic heterogeneity of the MPN group is becoming increasingly apparent. Patients with MPN frequently and routinely harbor a number of pathological mutations in various genes that affect epigenetic regulation, transcriptional control, and splicing. Non-driver mutations in MPN are genetic alterations that do not determine the disease phenotype (unlike JAK2, CALR, MPL), but are critical for prognosis, assessment of the risk of transformation, and selection of treatment strategies. In current practice, their detection is part of standard NGS panels for patients with myelofibrosis and other Ph-negative MPNs. These genes typically include ASXL1, DNMT3A, and TET2 with a relatively high frequency in >5% of patient samples across the MPN spectrum. Others, including CBL, SF3B1, EZH2, SRSF2, USAF1, TP53, and IDH1/2, have been detected in <2% of patients in large studies [3]. These mutations are routinely identified in other individuals across the range of myeloid malignancies and in the CHIP population. These mutations, which have been well characterized, represent only a small fraction of the overall mutational burden observed during aging in patients with MPNs using whole-genome sequencing approaches [4]. As larger cohorts of individuals continue to be analyzed, it is becoming apparent that the presence of certain mutations is associated with both the disease phenotype and ultimate prognosis. Patients with chronic phase SP and ET are significantly more likely to have no additional mutations compared with patients with PMF. The presence of mutations in certain genes has been significantly associated with the disease phenotype. For example, NFE2 mutations correlate with the SP phenotype, spliceosome component mutants, and epigenetic regulators EZH2 and ASXL1 are more frequently observed in PMF, whereas other genes, including IKZF1, are almost exclusively observed in blast phase. Early studies have shown clear prognostic implications of individual cooperative mutations. In a cohort of 483 European PMF patients who had validation in the American cohort, mutations in ASXL1, EZH2, and SRSF2 independently predicted reduced survival. IDH1/2 or