Genetic Aspects of Chronic Myeloid Leukemia: From Fundamental Mechanisms to Clinical Practice

In order to summarize current knowledge about the molecular genetic mechanisms of chronic myeloid leukemia (CML), a review of the key oncogene BCR:ABL1, the mechanisms of its formation and transformation, as well as the characteristics of transcriptional variants that encode the isoforms of the oncoprotein p210, p190, and p230. The pathophysiological effects of the constitutive tyrosine kinase activity of BCR:ABL1 and the signaling pathways (MAPK, PI3K/AKT, JAK/STAT) through which the proliferative and anti-apoptotic potential of the leukemic clone is realized are highlighted. Particular attention is paid to the clonal evolution of CML, the impact of additional high-risk cytogenetic abnormalities (HR-ACA) and somatic mutations (especially ASXL1) on prognosis and resistance to tyrosine kinase inhibitors (TKIs). It has been proven that AACs are markers of genomic instability and predictors of unfavorable outcomes. Data on pharmacogenetic and epigenetic mechanisms of resistance that shape the potential of the leukemic clone for long-term persistence have been summarized. The importance of comprehensive genomic profiling (OGM, NGS, LRS) in modern risk stratification has been emphasized.The need for the integration of molecular genetic markers into prognostic models aimed at achieving functional cure of CML, as well as the need for a personalized therapeutic strategy based on BCR:ABL1, clonal landscape, and pharmacogenetic characteristics of the patient, is justified. A promising direction is the development of combination therapy that includes targeted agents and epigenetic modulation agents aimed at eradicating leukemic stem cells.