Expanding the Spectrum of CSF3R Mutated Myeloid Neoplasm Beyond Chronic Neutrophilic Leukemia and Atypical Chronic Myeloid Leukemia: A Comprehensive Analysis of 13 Cases

Background: Genetic alterations of CSF3R, typically associated with chronic neutrophilic leukemia (CNL) and atypical chronic myeloid leukemia (aCML), rarely occur in other myeloid neoplasms. Methods: This study characterized the clinical, morphologic, cytogenetic, and molecular features of 13 patients with non-CNL non-aCML myeloid neoplasms with CSF3R alter-ations. Patients (median age 77 years) were categorized into myelodysplas-tic/myeloproliferative neoplasm (MDS/MPN) (n=5), acute leukemia (n=4), and other myeloid neoplasms (n=4) based on WHO 2022 and ICC criteria. Results: The CSF3R p.Thr618Ile mutation was most frequent (11/13), with additional pathogenic variants including p.Gln743Ter and frameshift mutations affecting the cyto-plasmic 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 (ASXL1, TET2) and splicing factors (SF3B1, SRSF2, ZRSR2), while acute leukemia cases showed alter-ations in JAK3, STAT3, and NRAS. Survival analysis revealed distinct patterns across the three diagnostic groups, with MDS/MPN having the poorest prognosis. Conclusion: This study expands the recognized spectrum of CSF3R-related myeloid neoplasms and highlights the clinical and molecular heterogeneity associated with these mutations, emphasizing the need for comprehensive molecular profiling and potential for targeted therapies.