COOPERATIVE EFFECTS OF U2AF1-S34 AND BCOR MUTATIONS IN MYELOID NEOPLASMS

A. ABUSHAMMA¹, A. MARUMO¹, Z. BRADY¹, S. Unlu¹, H. Gandicheruvu², V. VISCONTE¹ and J. MACIEJEWSKI¹

¹ Department of Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland Clinic, Cleveland, Ohio, USA
² Department of Internal Medicine, Sinai Hospital of Baltimore, George Washington University School of Medicine and Health Sciences Regional Medical Campus, Baltimore, Maryland, USA

INTRODUCTION

• U2AF1 mutations occur in approximately 7-11% of myeloid neoplasms and cluster at two zinc-finger hotspots, S34 and Q157.¹

• Both hotspot mutations have been associated with different co-mutations and clinical characteristics.¹

• In myelodysplastic syndromes (MDS), S34 mutations are predominant and are associated with worse overall survival and higher rates of leukemic transformation.¹˒²

• Distinct hematopoietic phenotypes have been described in U2AF1 mutant mice.³ However, hotspot-level clinical data across real-world patients with myeloid neoplasms remain incompletely defined.

AIMS

• The primary objective of this study is to investigate the clinical association and characteristics of U2AF1-S34 and Q157 mutations across myeloid neoplasms.

• The secondary objective is to define the prognostic impact of cooperating mutations.

METHOD

Study Cohort

• We analyzed 1,829 patients with myeloid neoplasms (CMML n=318, MDS n=1,186, MDS/MPN n=150, MPN n=27, AML n=148).

Mutation classification

• U2AF1 mutations were classified as S34 or Q157.

Data analysis

• Co-mutation frequencies were compared using Fisher's exact test.

• Multivariable Cox proportional hazards regression was adjusted for age, ASXL1, TP53, TET2, HMA therapy, and CPSS-Mol risk score for the CMML cohort.

CONCLUSIONS

• In this large cohort of myeloid neoplasms, S34 and Q157 exhibited markedly distinct co-mutation patterns: S34 with BCOR, Q157 with ASXL1.

• Patients with S34/BCOR co-mutation represent a previously uncharacterized adverse-risk group in myeloid neoplasms (median OS 10.1 months).

RESULTS

• In total, 196 patients (10.7%) carried U2AF1 variants: S34 in 98 (50%) and Q157 in 98 (50%).

• Compared to wild type, U2AF1-mutated patients had significantly lower OS (Figure 1A).

• Within the U2AF1-mutated cohort, both S34 and Q157 were independently associated with inferior OS (Figure 1A).

• BCOR mutations were significantly more common in S34 mutants, whereas ASXL1 mutations were more common in Q157 mutants (Figure 1B).

• Co-occurring U2AF1 S34 and BCOR mutations identified a high-risk subset (n = 31) with a median OS of 10.1 months, compared with 13.5 months for S34 alone, 35.8 months for BCOR alone, and 51.5 months for WT/WT (Figure 1C).

Figure 1. Hotspot-specific co-mutation patterns and overall survival in U2AF1-mutant myeloid neoplasms.
(A) Frequency of BCOR, ASXL1 and TP53 co-mutation by U2AF1 hotspot.
(B) Overall survival by U2AF1 hotspot.
(C) Overall survival by U2AF1-S34 and BCOR co-mutation.

ACKNOWLEDGEMENTS

We thank:

• VeloSano 11 Pilot Award (to V.V.)

• The Henry and Marilyn Taub Foundation (to V.V.)

CONTACT INFORMATION

Akram Abushamma: ABUSHAA3@ccf.org

Valeria Visconte: visconv@ccf.org

@VisconteValeria

REFERENCES

1. Badar T, Vanegas YAM, Nanaa A, et al. U2AF1 pathogenic variants in myeloid neoplasms and precursor states: distribution of co-mutations and prognostic heterogeneity. Blood Cancer J. 2023;13:149.

2. Wang H, Zhang N, Wu X, et al. Prognostic value of U2AF1 mutation in de novo myelodysplastic syndromes: a meta-analysis. Ann Hematol. 2019;98:2629–2639.

3. Alberti MO, Nonavinkere Srivatsan S, Shao J, et al. U2af1S34F and U2af1Q157R mutations induce distinct hematopoietic phenotypes in mice. Leukemia. 2026;40:1467–1481.