Chronic myeloid neoplasms harboring concomitant mutations in myeloproliferative neoplasm driver genes (JAK2/MPL/CALR) andSF3B1

JAK2,CALR, andMPLare myeloproliferative neoplasm (MPN)-driver mutations, whereasSF3B1is strongly associated with ring sideroblasts (RS) in myelodysplastic syndrome (MDS). Concomitant mutations ofSF3B1and MPN-driver mutations out of the context of MDS/MPN with RS and thrombocytosis (MDS/MPN-RS-T) are not well-studied. From the cases (<5% blasts) tested by NGS panels interrogating at least 42 myeloid neoplasm-related genes, we identified 18 MDS/MPN-RS-T, 42 MPN, 10 MDS, and 6 MDS/MPN-U cases with anSF3B1and an MPN-driver mutation. Using a 10% VAF difference to define SF3B1-dominant, MPN-mutation dominant, and no dominance, the majority of MDS/MPN-RS-T clustered in SF3B1-dominant and no dominance regions. Aside from parameters as thrombocytosis and >= 15% RS required for RS-T, MDS also differed in frequent neutropenia, multilineage dysplasia, and notably more cases with <10% VAF of MPN-driver mutations (60%,p = 0.0346); MPN differed in more frequent splenomegaly, myelofibrosis, and higher VAF of MPN-driver mutations. Gray zone cases with features overlapping MDS/MPN-RS-T were observed in over one-thirds of non-RS-T cases. This study shows that concomitantSF3B1and MPN-driver mutations can be observed in MDS, MPN, and MDS/MPN-U, each showing overlapping but also distinctively different clinicopathological features. Clonal hierarchy, cytogenetic abnormalities, and additional somatic mutations may in part contribute to different disease phenotypes, which may help in the classification of gray zone cases.

Automated summary

The study indicates that concomitant SF3B1 and MPN-driver mutations can be found in MDS, MPN, and MDS/MPN-U, each presenting overlapping yet distinctive clinicopathological features. Gray zone cases with overlapping features of MDS/MPN-RS-T were observed in over one-thirds of non-RS-T cases.