RECURRENT MUTATIONS IN THE U2AF1 SPLICING FACTOR IN MYELODYSPLASTIC SYNDROMES

By T. Graubert, D. Shen, Li Ding, Theresa Okeyo-Owuor, Cara L. Lunn, J. Shao, K. Krysiak, C. Harris, Daniel C. Koboldt, David E. Larson and 20 more. Nature Genetics, 2011

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Myelodysplastic syndromes (MDS) are hematopoietic stem cell disorders that often progress to chemotherapy-resistant secondary acute myeloid leukemia (sAML). We used whole-genome sequencing to perform an unbiased comprehensive screen to discover the somatic mutations in a sample from an individual with sAML and genotyped the loci containing these mutations in the matched MDS sample. Here we show that a missense mutation affecting the serine at codon 34 (Ser34) in U2AF1 was recurrently present in 13 out of 150 (8.7%) subjects with de novo MDS, and we found suggestive evidence of an increased risk of progression to sAML associated with this mutation. U2AF1 is a U2 auxiliary factor protein that recognizes the AG splice acceptor dinucleotide at the 3′ end of introns, and the alterations in U2AF1 are located in highly conserved zinc fingers of this protein. Mutant U2AF1 promotes enhanced splicing and exon skipping in reporter assays in vitro. This previously unidentified, recurrent mutation in U2AF1 implicates altered pre-mRNA splicing as a potential mechanism for MDS pathogenesis.

Subfields: Hematology, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/c95aaa7eaacd879cd513799aeaec95a2b75cc9e1

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Citations in the corpus

Clonal Architecture of Secondary Acute Myeloid Leukemia (2012, background): “The founding clone contains del(17), del(20q), and cluster 1 single-nucleotide variants (SNVs) (yellow data points in Panels A and C), whereas a subclone also contains del(5), monosomy 17, and cluster 2 SNVs (orange data points in Panels A and C).”
Mapping the hallmarks of lung adenocarcinoma with massively parallel sequencing (2012, background): “Identical c.101C > T, p.S34F mutations were seen in four of five U2AF1 mutant cases (Figure 3A); this is the exact mutation re- 1112 Cell 150, 1107–1120, September 14, 2012 ª2012 Elsevier Inc. ported in myelodysplastic syndrome (MDS) (Graubert et al., 2012; Yoshida et al., 2011).”
RNA splicing factors as oncoproteins and tumor suppressors (2016, unknown): “The t(1;9)(p34;q34) fusing ABL1 with SFPQ, a pre-mRNA processing gene, is recurrent in acute lymphoblastic leukemias.”
Comprehensive Analysis of Alternative Splicing Across Tumors from 8,705 Patients (2018, background): “, 2014) or myelodysplastic syndromes (Graubert et al., 2012).”
Clinical and biological implications of driver mutations in myelodysplastic syndromes. (2013, result): “These findings replicate previous studies.(5,9,11,35-37,45,46) We assessed whether the effects on clinical outcome of a given gene differed by whether mutations were clonal or subclonal.”
Diagnosis and treatment of primary myelodysplastic syndromes in adults: recommendations from the European LeukemiaNet. (2013, background): “These genes include SF3B1, SRSF2, U2AF35 and ZRSR2, and with a lower frequency, SF3A1, SF1, U2AF65 and PRPF40B.36-38,69 Table 5 reports a list of recurrently mutated genes in MDS.”
A census of human RNA-binding proteins (2014, background): “U2AF1, U2AF1L4 ZRSR1, ZRSR2 myelodysplastic syndrome missense mutation (Graubert et al., 2012)”