Additional myelodysplasia-related gene mutations alter clinical presentation and worsen prognosis in patients with SRSF / TET2 co-mutated myeloid neoplasms

SRSF2/TET2 is a common co-mutation characterized by monocytosis across many myeloid neoplasms, including CMML. Myelodysplasia-related gene (MRG) mutations, including SRSF2, SF3B1, U2AF1, ZRSR2, ASXL1, EZH2, BCOR, and STAG2, are key contributors to leukemic transformation, though their interactions with other mutations are understudied. In this retrospective cohort study, we examined the clinical and prognostic impact of additional mutated MRGs in 412 patients with SRSF2/TET2 co-mutated neoplasms, identified from the Moffitt Next Gen Sequencing Database. The majority of patients (55%) had at least one additional MRG mutation, which was associated with decreased monocytosis, increased anemia, and poorer overall survival (10.941 vs. 23.787 months, p < 0.001). ASXL1 was the most common MRG mutation and independently predicted worse survival. Patients with additional MRGs were more likely to have AML arising from CMML (12.3% vs 5.9%, p = 0.029). These findings may be used in future clinical practice to provide better prognosis and treatment stratification.