Frequency, genomic characteristics, and effects on splicing of RNA splicing factor mutations seen in hematologic malignancies. (A) Histogram of mutations in the most commonly mutated RNA splicing factors across hematologic malignancies. AML-MRC, acute myeloid leukemia with myelodysplasia-related changes; BPDCN, blastic plasmacytoid dendritic cell neoplasm; CLL: chronic lymphocytic leukemia; CMML, chronic myelomonocytic leukemia; RARS, refractory anemia with ring sideroblasts; RCMD-RS, refractory cytopenia with multilineage dysplasia and ring sideroblasts. (B) Location and relative frequency of mutations in SF3B1 and U2AF1 in myeloid neoplasms, CLL, and solid tumors. (C) Location and relative frequency of mutations in SRSF2 with indication of exact amino acid substitutions at mutated residues. (D) Location and relative frequency of mutations in ZRSR2 displaying known frameshift and insertion/deletion mutations only. (E) Location of recurrent mutations in the gene (or genes) encoding the U1 snRNA affect its third nucleotide, which makes critical base pairs with the 5' splice site. (F) The most frequent mutations in HNRNPH1 cluster in the introns surrounding exon 4 and promote inclusion of this exon. HNRNPH1 mutations in this region occur entirely as single-nucleotide point mutations (as indicated by the brown lollipops). Repression of exon 4 induces a NMD-inducing isoform of HNRNPH1, while inclusion of exon 4 promotes stable HNRNPH1 expression. WT, wild-type.