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U2AF1 pathogenic variants in myeloid neoplasms and precursor states: distribution of co-mutations and prognostic

Talha Badar1, Yenny A Moreno Vanegas2, Ahmad Nanaa3,4

  • 1Division of Hematology-Oncology and Bone Marrow Transplant Program, Mayo Clinic, Jacksonville, FL, 32224, USA. badar.talha@mayo.edu.

Blood Cancer Journal
|September 22, 2023
PubMed

Insights

U2AF1 mutations in myeloid malignancies show distinct prognostic impacts. The Q157P variant is associated with worse survival in high-risk disease, unlike the S34F variant.

Area of Science:

  • Hematology
  • Oncology
  • Molecular Biology

Background:

  • U2AF1 mutations (MT) are recognized for their genotypic and prognostic heterogeneity in myelofibrosis (MF) and myelodysplastic syndromes (MDS).
  • Understanding the specific roles of different U2AF1 variants and their co-mutational landscapes is crucial for refining prognostication and treatment strategies in myeloid malignancies.

Purpose of the Study:

  • To define the prevalence and co-mutational profiles of U2AF1 pathogenic variants across a spectrum of myeloid malignancies, including clonal cytopenia of undetermined significance (CCUS), MDS, MDS/acute myeloid leukemia (AML), and AML.
  • To investigate the prognostic significance of different U2AF1 variants, particularly S34F and Q157P, in patients with high-risk disease (≥10% blasts).
  • To identify additional genetic factors and therapeutic interventions impacting overall survival (OS) in U2AF1-mutated myeloid neoplasms.

Main Methods:

  • Retrospective analysis of 179 patients with U2AF1 mutations across CCUS, MDS, MDS/AML, and AML.
  • Detailed characterization of U2AF1 variant types (S34, Q157, others) and concurrent mutations (ASXL1, BCOR, RUNX1, TET2, DNMT3A, NRAS/KRAS, TP53, JAK2, SETBP1).
  • Survival analysis, including transplant-adjusted multivariable analysis, to assess the impact of U2AF1 variants, co-mutations, and allogeneic hematopoietic stem cell transplantation (HSCT) on overall survival.

Main Results:

  • U2AF1 variants S34F (60%) and Q157P (35%) were the most frequent. Concurrent mutations were more common with Q157P (91%), while abnormal karyotype was more frequent with S34F (70%).
  • In high-risk disease (≥10% blasts), Q157P was associated with significantly worse median OS (14.2 months) compared to S34F (37.1 months; P=0.008).
  • Transplant-adjusted analysis confirmed Q157P as detrimental to survival (P=0.01) and identified JAK2 mutations as an additional risk factor (P=0.02). Allogeneic HSCT favorably impacted OS (HR: 0.16, P=0.007).

Conclusions:

  • The study delineates the distinct prevalence and co-mutational patterns of U2AF1 variants in various myeloid neoplasms.
  • Prognostic heterogeneity exists among U2AF1 mutations, with Q157P conferring a worse prognosis in high-risk AML and MDS/AML.
  • Identification of specific U2AF1 variants and co-mutations like JAK2, alongside the benefit of allogeneic HSCT, aids in risk stratification and personalized management of U2AF1-mutated myeloid malignancies.

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