by Bartlomiej Przychodzen, Andres Jerez, Kathryn Guinta, Mikkael A

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Spliceosome mutations in myeloid neoplasms

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Patterns of missplicing due to somatic U2AF1 mutations in myeloid neoplasms by Bartlomiej Przychodzen, Andres Jerez, Kathryn Guinta, Mikkael A. Sekeres, Richard Padgett, Jaroslaw P. Maciejewski, and Hideki Makishima Blood Volume 122(6):999-1006 August 8, 2013 ©2013 by American Society of Hematology

Distribution and frequency of U2AF1 mutations across gene domains and different hematological malignancies. Distribution and frequency of U2AF1 mutations across gene domains and different hematological malignancies. (A) Three isoforms of U2AF1 are shown with the 2 zinc finger domains (ZNF) and the RNA recognition motif (RRM) highlighted. Almost all identified U2AF1 missense mutations are located in 1 of the 2 ZNF domains. (B) Comparison of the frequency of U2AF1 mutations between different hematological malignancies. MDS/MPN and high-risk MDS (RAEB1/2) showed the most frequent mutations (14% and 13%, respectively), whereas primary AML showed the least (6%). RA, refractory anemia; RCMD, refractory cytopenia with multilineage dysplasia; RCMD-RS, refractory cytopenia with multilineage dysplasia with ring sideroblasts; RCUD, refractory cytopenia with unilineage dysplasia. Bartlomiej Przychodzen et al. Blood 2013;122:999-1006 ©2013 by American Society of Hematology

Differences of exon usage frequencies in genes that were identified. Differences of exon usage frequencies in genes that were identified. Exon skipping frequencies were based on RNAseq data, averaged and presented as bar graphs. (A) Bars in dark blue represent U2AF1 mutants; dark brown bars represent WT. The order of genes was determined using the average difference between U2AF1 mutant and WT exon skipping frequency. (B) Detailed frequency of exon skipping of all exons screened for PTBP1 (upper panel) and CEP164 (lower panel). Additional mutational information is depicted for both selected genes. CEP164 lower panel contains additional SNP karyotyping data depicting samples that had the CEP164 locus deleted (highlighted in red). Bartlomiej Przychodzen et al. Blood 2013;122:999-1006 ©2013 by American Society of Hematology

Transcriptional analysis of patients with splicing factor mutations. Transcriptional analysis of patients with splicing factor mutations. (A) Comparison of levels of U2AF1 mRNA between U2AF1 mutants, WT cases, and WT cases with low expression of U2AF1 (red, blue, and green colors, respectively). The mean expression level is indicated by the dashed line. (B) Exon skipping levels in 3 genes comparing U2AF1 mutants, WT, and WT with low expression levels (red, blue, and green bars, respectively). (C) Validation of RNAseq results on exon 7 of the CEP164 gene using an independent set of patients by RT-PCR. (D) Comparison of exon skipping levels between patients bearing mutations in different spliceosomal factors: SF3B1, SRSF2, U2AF26, and U2AF1. ATR, ataxia telangiectasia and Rad3-related. Bartlomiej Przychodzen et al. Blood 2013;122:999-1006 ©2013 by American Society of Hematology

Frequencies of nucleotides surrounding 39 and 59 splice sites adjacent to exons affected by U2AF1 mutations. Frequencies of nucleotides surrounding 39 and 59 splice sites adjacent to exons affected by U2AF1 mutations. Exons that were more often skipped (A) or more often retained (B) in U2AF1 mutants were combined into 2 groups, and the splice site consensus sequences were derived. Adjacent splice sites were analyzed as a control set (C). Nucleotide frequencies are represented using WebLogo software. The height of each stack represents the information content of that position in bits. The height of each letter represents the frequency of occurrence of each nucleotide. Bartlomiej Przychodzen et al. Blood 2013;122:999-1006 ©2013 by American Society of Hematology