Chronic myelomonocytic leukemia with double activating <i>KRAS</i> mutations: molecular characterization of an uncommon case

Abstract Chronic myelomonocytic leukemia (CMML) is a clonal myelodysplastic/myeloproliferative neoplasm characterized by persistent monocytosis and heterogeneous risk of progression to acute leukemia. Mutations within the RAS/MAPK signaling pathway, particularly involving KRAS, are linked to a proliferative disease phenotype and adverse prognosis. We report the first Colombian CMML case harboring two concurrent activating KRAS mutations (p.G12S and p.G13D). Both variants were detected at variant allele frequencies of 17% and 21% in a female patient in her late 50s presenting with marked leukocytosis, anemia, and thrombocytopenia. The coexistence of these mutations suggests synergistic hyperactivation of the RAS/MAPK pathway, likely driving clinical aggressiveness and therapeutic resistance. This case delineates a rare molecular subgroup within CMML and highlights the critical role of comprehensive genomic profiling to improve prognostic accuracy and inform precision medicine approaches.