Additional myelodysplasia-related gene mutations alter clinical presentation and worsen prognosis in patients with/co-mutated myeloid neoplasms.
Key claim: In TET2-co-mutated myeloid neoplasms, additional myelodysplasia-related gene mutations (most often ASXL1) are common, reduce monocytosis, increase anemia, roughly halve overall survival, and raise the rate of AML arising from CMML.
Abstract
is a common co-mutation characterized by monocytosis across many myeloid neoplasms, including CMML. Myelodysplasia-related gene (MRG) mutations, including, and, 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/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, < 0.001).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%, = 0.029). These findings may be used in future clinical practice to provide better prognosis and treatment stratification.
Why this matters
This finding sharpens subtype-specific prognosis by showing that within TET2-co-mutated myeloid neoplasms — a group that heavily overlaps CMML and MDS/MPN overlap territory — the presence of additional myelodysplasia-related mutations (most often ASXL1) is not a minor modifier but a major axis: it changes the clinical face of the disease (less monocytosis, more anemia), halves survival, and roughly doubles leukemic transformation risk. It reinforces the emerging pattern across MPN subtypes that ASXL1 and other HMR co-mutations dominate outcome, and argues for co-mutation-aware risk stratification even in TET2-mutated disease that might otherwise appear indolent.