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

• Published in: Blood cancer journal (New York) 2023-09, Vol.13 (1), p.149-7, Article 149
• Main Authors: Badar, Talha, Vanegas, Yenny A. Moreno, Nanaa, Ahmad, Foran, James M., Al-Kali, Aref, Mangaonkar, Abhishek, Murthy, Hemant, Alkhateeb, Hassan B., Viswanatha, David, He, Rong, Shah, Mithun, Yi, Cecilia Arana, Litzow, Mark R., Gangat, Naseema, Tefferi, Ayalew, Patnaik, Mrinal M.
• Format: Article
• Language: English
• Subjects: 631/67/1990/1673; 692/699/67/68/2486; Biomedical and Life Sciences; Biomedicine; Cancer Research; Hematology; Humans; Leukemia, Myeloid, Acute - genetics; Leukemia, Myeloid, Acute - therapy; Mutation; Myelodysplastic syndromes; Myelodysplastic Syndromes - genetics; Myeloproliferative Disorders; Oncology; Prognosis; RNA-Binding Proteins; Splicing Factor U2AF - genetics; Transplants & implants
• ISSN: 2044-5385; 2044-5385
• DOI: 10.1038/s41408-023-00922-7

We have previously recognized the genotypic and prognostic heterogeneity of U2AF1 mutations (MT) in myelofibrosis (MF) and myelodysplastic syndromes (MDS). In the current study, we considered 179 U2AF1 -mutated patients with clonal cytopenia of undetermined significance (CCUS; n  = 22), MDS ( n  = 108), MDS/acute myeloid leukemia (AML; n  = 18) and AML ( n  = 31). U2AF1 variants included S34 (60%), Q157 (35%), and others (5%): corresponding mutational frequencies were 45%, 55%, and 0% in CCUS; 57%, 39%, and 4% in MDS; 61%, 33%, and 6% in MDS/AML; and 55%, 35% and 10% in AML ( P  = 0.17, 0.36 and 0.09), respectively. Concurrent mutations included ASXL1 (37%), BCOR (19%), RUNX1 (14%), TET2 (15%), DNMT3A (10%), NRAS / KRAS (8%), TP53 (8%), JAK2 (5.5%) and SETBP1 (5%). The two most frequent U2AF1 MT were S34F ( n  = 97) and Q157P ( n  = 46); concurrent MT were more likely to be seen with the latter (91% vs 74%; P  = 0.01) and abnormal karyotype with the former (70% vs 62%; P  = 0.05). U2AF1 S34F MT clustered with BCOR ( P  = 0.04) and Q157P MT with ASXL1 ( P  = 0.01) and TP53 ( P  = 0.03). The median overall survival (OS) in months was significantly worse in AML (14.2) vs MDS/AML (27.3) vs MDS (33.7; P  = 0.001); the latter had similar OS with CCUS (30.0). In morphologically high-risk disease ( n  = 49), defined by ≥10% blood or bone marrow blasts (i.e., AML or MDS/AML), median OS was 14.2 with Q157P vs 37.1 months in the presence of S34F ( P  = 0.008); transplant-adjusted multivariable analysis confirmed the detrimental impact of Q157P ( P  = 0.01) on survival and also identified JAK2 MT as an additional risk factor ( P  = 0.02). OS was favorably affected by allogeneic hematopoietic stem cell transplantation (HR: 0.16, 95% CI; 0.04-0.61, P  = 0.007). The current study defines the prevalence and co-mutational profiles of U2AF1 pathogenic variants in AML, MDS/AML, MDS, and CCUS, and suggests prognostic heterogeneity in patients with ≥10% blasts.