Impact of <i>U2AF1</i> Pathogenic Variants on Prognosis of Myelodysplastic Neoplasms With <i>RUNX1</i> Mutation

ABSTRACT RUNX1 is one of the most commonly mutated genes in myelodysplastic neoplasms (MDS) and essential for hematopoiesis. However, clinical phenotype features of RUNX1 mutated patients and the interaction between RUNX1 and other genes mutations remains incompletely explored. We enrolled 1473 consecutive adult patients with primary MDS to investigate the laboratory, genomic characteristics, and survival of RUNX1 ‐mutated MDS subjects. We found that RUNX1 mutations are associated with older age (median, 59 vs. 56 years, p = 0.007), lower platelet counts (median, 50 × 10 9 /L vs. 66 × 10 9 /L; p &lt; 0.001), higher bone marrow blasts (median, 6.0% vs. 2.5%, p &lt; 0.001) and a higher proportion of micro‐megakaryocytes (median, 26.0% vs. 18.7%, p &lt; 0.001). Additionally, our data showed a correlation between the variant allele frequency (VAF) of RUNX1 mutations and proportion of micro‐megakaryocytes ( r = 0.242, p = 0.006), suggesting RUNX1 mutations burden was associated with dysmegakaryopoiesis. Mutations in ASXL1 , SRSF2 , EZH2 and NRAS were significantly more frequent in RUNX1 ‐mutated patients compared with those without RUNX1 mutations (adjusted p &lt; 0.05). RUNX1 ‐mutated patients exhibited poorer overall survival (median OS 18 months vs. 51 month, p &lt; 0.001), while U2AF1 co‐mutations were associated with a relatively better prognosis (median OS 34 months vs. 17 months, p = 0.003), indicating a potential modifying effect of U2AF1 on the outcome of RUNX1 ‐mutated patients.