RNA-seq analyses of telomere dysfunctional CMP identified aberrantly spliced transcripts linked to pathways relevant to MDS pathogenesis such as genome stability, DNA repair, chromatin remodeling, and histone modification, which are also enriched in mouse CMP haploinsufficient for SRSF2 and in CD34(+) CMML patient cells harboring SRSF2 mutation.
Here, we review recent biologic observations that support the current CMML WHO classification, such as the high frequency of SRSF2 and ASXL1 mutations compared with MDS and critical dependence of CMML cells on granulocyte-macrophage colony-stimulating factor signaling.
SRSF2 mutations were identified in 16 (44%) of 36 CMMLs, including 1 of 3 cases with associated systemic mastocytosis, 4 (20%) of 20 Ph- MPN, and 1 (4.5%) of 22 MDS.
We conclude that SRSF2 is the most frequently mutated spliceosome gene in CMML but neither it nor SF3B1 or U2AF35 mutations are prognostically relevant.
We investigated the contribution of U2AF1, SRSF2 and SF3B1 mutations in the pathogenesis of chronic myelomonocytic leukemia and closely related diseases.
Among spliceosome component mutations, those involving SF3B1 are most frequent in myelodysplastic syndromes with ring sideroblasts (MDS-RS; ∼ 75% incidence) and SRSF2 in chronic myelomonocytic leukemia (∼ 28% incidence).