U2AF1 Mutant Clonal Hematopoiesis Is Infrequent, Context Dependent, and Commonly Co-Occurs with BCOR Mutations

Background: U2AF1 is an important component of the spliceosome complex required for pre-mRNA splicing. Mutations in U2AF1 have been described in myeloid neoplasms (5-10%), with variants causing specific alterations in 3′ splice site recognition. U2AF1 mutations predominantly occur at two hotspots (S34, Q157) located in zinc finger regions. While characteristics of U2AF1 mutant myeloid neoplasms have been described, their phenotype in clonal hematopoiesis (CH) remains to be elucidated.

Methods: In 2017, Mayo Clinic launched a prospective CH clinic. After IRB approval, the CH and myeloid neoplasms databases were queried for patients meeting criteria for U2AF1 CH, including CH of indeterminate potential (CHIP) and clonal cytopenia(s) of undetermined significance (CCUS) [Xie et al Leuk Research]. Individuals with a diagnosis of myelodysplastic syndrome (MDS), myeloproliferative neoplasms (MPN), or acute myeloid leukemia (AML) were excluded. Clinical characteristics and outcomes were retrospectively abstracted. U2AF1 gene sequencing was carried out using a targeted capture assay (250-500 x coverage) and included all coding regions and splice acceptor/donor sites for U2AF1.

Results: Twenty (6%) of 330 successive patients met criteria for U2AF1 mutant CH, of which, 19 (95%) met criteria for U2AF1 mutant CCUS. Median age at CH diagnosis was 71 years (range, 29-92) with 75% being male. Fifteen (75%) had mutations involving the S34 hotspot, while the remainder (25%) had Q157 mutations. Within limitations of a small sample size, there were no significant differences between the two U2AF1 hot spot sites with regards to clinical and laboratory features and concurrent mutations. The median U2AF1 variant allele frequency (VAF) was 16% (2-38%). Median blood indices and mutational characteristics are noted in Panel 1. Six (30%) patients presented with autoimmune/inflammatory features that were poorly defined.

Six (30%) patients had prior exposure to radiation/radioisotope therapy (one with concurrent chemotherapy and one with Lutetium Dotatate for neuroendocrine tumor) and 1 (5%) had an underlying telomere biology disorder (germline TERC mutation). Thirteen (65%) patients had ≥1 co-occurring somatic mutation; 7 (35%) with 1, 5 (25%) with 2 and 1 (5%) with 3 co-occurring mutations, respectively. BCOR was most frequently co-mutated with U2AF1, with 7 (35%) demonstrating BCOR co-mutations (6 with S34 and 1 Q157), 86% male (BCOR location on X-chromosome), with a median VAF of 23% (range, 6-80%). All BCOR co-mutations resulted in truncation of the protein. Truncating ASXL1 co-mutations were seen in 3 (15%) patients, while DNMT3A and co-occurring splicing mutations were absent.

Four patients (20%) underwent myeloid transformation (3 MDS, 1 AML), with the median time to transformation being 8 months (range, 4-24 months). All 4 (100%) patients with transformation had prior exposure to radiation therapy and 2 (50%) had concurrent BCOR mutations. At last follow up, 7 (35%) deaths were documented.

Single cell proteogenomic data in the U2AF1/BCOR co-mutant cases will be available at the time of abstract presentation.

Conclusion:U2AF1 mutant CH is infrequent, commonly presents with cytopenias, is context dependent with prior radiation exposure being seen in 30%, is more common in males (75%) and frequently co-occurs with truncating BCOR mutations (35%; 86% in males). Concurrent DNMT3A mutations were not seen in the cohort and 20% of patients progressed to myeloid neoplasms within 24 months of detection.

Mangaonkar:Bristol Myers Squibb: Research Funding. Al-Kali:Astex: Other: research support to institution. He:Kura Oncology, Inc: Consultancy. Foran:AbbVie, Actinium, Aptose, Astex, H3Biosciences, Kura Oncology, Trillium, Xencor: Research Funding; Novartis, Servier, Pfizer, BMS, Taiho: Other: Formal Advisory Activities. Patnaik:Kura Oncology, Stem Line Pharmaceuticals: Research Funding.