U2AF1 encodes for the small subunit of the U2 auxiliary factor, which is a non-small nuclear ribonucleoprotein (non-snRNP) required for the binding of U2 snRNP to the pre-mRNA branch site and plays critical role in RNA splicing. U2AF1 is one of several spliceosome complex genes frequently mutated in a variety of hematologic malignancies. Two hotspot mutations (S34 in exon 2 and Q157 in exon 6) occur within the two zinc-finger domains of the U2AF1 protein. These mutations have been reported in approximately 4- 9% of chronic myelomonocytic leukemia, 8-11% of cases of myelodysplastic syndrome (typically without ring sideroblasts), 16% of primary myelofibrosis, 12% of blastic plasmacytoid dendritic cell neoplasm, 4% of acute myeloid leukemia and 1% of essential thrombocythemia. U2AF1 mutations are associated with an unfavorable prognosis in myelodysplastic syndrome (NCCN Guidelines for Myelodysplastic Syndromes) and essential thrombocythemia, and decreased response to lenalidomide in myeloid neoplasms with and without del(5q). U2AF1 mutations are also reported to be highly specific for secondary acute myeloid leukemia, and may also be helpful in identifying a subset of therapy-related AML or elderly de novo AML with worse clinical outcomes. U2AF1 mutations have been associated with altered splicing patterns in vitro and in vivo, and may play a significant role in the pathogenesis of myeloid malignancies due to selective mis-splicing of tumor-associated genes.
- Wu SJ, et al. Clinical implications of U2AF1 mutation in patients with myelodysplastic syndrome and its stability during disease progression. Am J Hematol 2013;88(11):E277-82
- Patnaik MM, et al. Spliceosome mutations involving SRSF2, SF3B1, and U2AF35 in chronic myelomonocytic leukemia: prevalence, clinical correlates, and prognostic relevance. Am J Hematol 2013;88(3):201-6
- Thol F, et al. Frequency and prognostic impact of mutations in SRSF2, U2AF1, and ZRSR2 in patients with myelodysplastic syndromes. Blood 2012;119(15):3578-84
- Graubert TA, et al. Recurrent mutations in the U2AF1 splicing factor in myelodysplastic syndromes. Nat Genet 2011;44(1):53-7
- Yoshida K, et al. Frequent pathway mutations of splicing machinery in myelodysplasia. Nature 2011;478(7367):64-9
- Larsson CA, et al. The changing mutational landscape of acute myeloid leukemia and myelodysplastic syndrome. Mol Cancer Res 2013;11(8):815-27
- Tefferi A, et al. CALR and ASXL1 mutations-based molecular prognostication in primary myelofibrosis: an international study of 570 patients. Leukemia 2014;28(7):1494-500
- Menezes J, et al. Exome sequencing reveals novel and recurrent mutations with clinical impact in blastic plasmacytoid dendritic cell neoplasm. Leukemia 2014;28(4):823-9
- Haferlach T, et al. Landscape of genetic lesions in 944 patients with myelodysplastic syndromes. Leukemia 2014;28(2):241-7
- Elena C, et al. Integrating clinical features and genetic lesions in the risk assessment of patients with chronic myelomonocytic leukemia. Blood 2016;128(10):1408-17
- Metzeler KH, et al. Spectrum and prognostic relevance of driver gene mutations in acute myeloid leukemia. Blood 2016;128(5):686-98
- Tefferi A, et al. Targeted deep sequencing in polycythemia vera and essential thrombocythemia. Blood Adv 2016;1(1):21-30
- Negoro E, et al. Molecular predictors of response in patients with myeloid neoplasms treated with lenalidomide. Leukemia 2016;30(12):2405-2409
- Lindsley RC, et al. Acute myeloid leukemia ontogeny is defined by distinct somatic mutations. Blood 2015;125(9):1367-76
- Ilagan JO, et al. U2AF1 mutations alter splice site recognition in hematological malignancies. Genome Res 2015;25(1):14-26
- Shirai CL, et al. Mutant U2AF1 Expression Alters Hematopoiesis and Pre-mRNA Splicing In Vivo. Cancer Cell 2015;27(5):631-43