Chronic myelomonocytic leukemia without increased classical monocyte subsets exhibits a distinct genetic profile, including frequent CBL mutations

Abstract Objectives To characterize the genetic profiles of chronic myelomonocytic leukemia (CMML) cases that do not exhibit increased classical monocyte (CM) subsets in ­peripheral blood. Methods A total of 174 patients with CMML who were treatment‑naive for hypomethylating agents and had undergone next‑generation sequencing (NGS) testing were analyzed. Among these, 152 patients (87.4%) demonstrated increased CM subsets (94%) by flow cytometry (CM group), while 22 patients (12.6%) did not show increased CM subsets (≤94%) (non‑CM group). Results Patients in the CM and non‑CM groups exhibited comparable demographic characteristics, complete blood count parameters, CMML subtype (myelodysplastic vs myeloproliferative), and disease grade (CMML‑1 vs CMML‑2). The NGS analysis revealed significant enrichment of CBL (45.5% vs 11.2%, P .001), IDH2 (18.2% vs 4.6%, P = .035), RAS pathway gene mutations (59.1% vs 34.2%, P = .033), and a lower frequency of TET2 mutations (40.9% vs 67.1%, P = .031) in the non‑CM group compared with the CM group. Patients with CMML in the non‑CM group also exhibited fewer cytogenetic abnormalities compared with those in the CM group (0% vs 22.5%, P = .039). Both non-CM and CBL-mutated CMML showed higher expression of HLA-DR by flow cytometry. No statistically significant differences were observed between the 2 groups in overall survival or acute myeloid leukemia–free survival. Conclusions Chronic myelomonocytic leukemia without increased CM subsets is associated with a distinct genetic profile characterized by enrichment of CBL mutations. Mechanistically, we hypothesize that CBL mutations promote proinflammatory signaling that contributes to normalization of CM partitioning.