Impact of U2AF1 Pathogenic Variants on Prognosis of Myelodysplastic Neoplasms With RUNX1 Mutation

Area of Science:

• Hematology
• Oncology
• Genetics

Background:

• RUNX1 is a crucial gene for hematopoiesis and frequently mutated in myelodysplastic neoplasms (MDS).
• The clinical characteristics and prognostic implications of RUNX1 mutations in MDS are not fully understood.

Purpose of the Study:

• To investigate the laboratory, genomic, and survival characteristics of adult patients with primary MDS and RUNX1 mutations.
• To explore the association between RUNX1 mutation variant allele frequency (VAF) and specific MDS phenotypes.
• To identify co-occurring mutations and their impact on prognosis in RUNX1-mutated MDS.

Main Methods:

• Analysis of 1473 adult patients with primary MDS.
• Comparison of laboratory and genomic features between RUNX1-mutated and non-mutated MDS patients.
• Survival analysis (overall survival) stratified by mutation status and co-mutations.

Main Results:

• RUNX1 mutations were associated with older age, lower platelet counts, increased bone marrow blasts, and a higher proportion of micro-megakaryocytes.
• A positive correlation was observed between RUNX1 VAF and micro-megakaryocyte proportion, suggesting dysmegakaryopoiesis.
• Co-mutations in ASXL1, SRSF2, EZH2, and NRAS were more frequent in RUNX1-mutated patients.
• RUNX1-mutated MDS patients had significantly poorer overall survival (18 months vs. 51 months).
• U2AF1 co-mutations were associated with a better prognosis in RUNX1-mutated patients (34 months vs. 17 months).

Conclusions:

• RUNX1 mutations define a distinct clinical and genomic subgroup within MDS.
• The burden of RUNX1 mutations correlates with impaired megakaryopoiesis.
• RUNX1 mutations portend a poor prognosis, but U2AF1 co-mutations may modify this outcome.