Expanding the Spectrum of -Mutated Myeloid Neoplasm Beyond Chronic Neutrophilic Leukemia and Atypical Chronic Myeloid Leukemia: A Comprehensive Analysis of 13 Cases.

Genetic alterations in , typically associated with chronic neutrophilic leukemia (CNL) and atypical chronic myeloid leukemia (aCML), rarely occur in other myeloid neoplasms. This study characterized the clinical, morphologic, cytogenetic, and molecular features of 13 patients with non-CNL non-aCML myeloid neoplasms with alterations. Patients (median age, 77 years) were categorized into groups with a myelodysplastic/myeloproliferative neoplasm (MDS/MPN) (n = 5), acute leukemia (n = 4), and other myeloid neoplasms (n = 4) based on the WHO 2022 and ICC criteria. The p.618 mutation was most frequent (11/13), with additional pathogenic variants including p.743 and frameshift mutations affecting the cytoplasmic tail. Variant allele frequencies (VAFs) ranged from 2% to 49%, with the highest median VAF in the MDS/MPN group. Co-mutations varied by subtype; MDS/MPN, NOS, and CMML cases frequently harbored mutations in epigenetic regulators (, ) and splicing factors (, , ), while acute leukemia cases showed alterations in , , and . Survival analysis revealed distinct patterns across the three diagnostic groups, with MDS/MPN having the poorest prognosis. This study expands the recognized spectrum of -related myeloid neoplasms and highlights the clinical and molecular heterogeneity associated with these mutations, emphasizing the need for comprehensive molecular profiling and the potential for targeted therapies.