Components of the spliceosome that are recurrently mutated in MDS and their relationship to disease-associated clinicopathological features. Acquired spliceosome mutations, especially in components important for 3′ splice site recognition, are observed in more than one-half of MDS patients, particularly those with ring sideroblasts (SF3B1) or myeloproliferative neoplasm overlap features (SRSF2). The 3 most commonly mutated splicing factors (U2AF1, SRSF2, SF3B1) are depicted in red, whereas other less commonly observed mutations (ZRSR2, SF3A1, U2AF2, PRPF40B, LUC7L2, SF1, SAP130) are depicted in orange-yellow. These mutations result in a wide variety of alternative and aberrant splicing events in CD34⁺ or more differentiated cells, which can result in reduced, increased, or altered function in encoded proteins important for a broad range of cellular pathways. It is not yet clear how alterations in these pathways as a consequence of aberrant and alternative splicing result in MDS-associated clinical features, including dysplastic blood cell morphology, marrow failure, and clonal outgrowth and instability. ER, endoplasmic reticulum. Photomicrographs in lower left courtesy of ASH Image Bank (imagebank.hematology.org, #2117, 60051, 60183, and 61365) and are copyright the American Society of Hematology. The lower right section of the figure has been modified from Figure 2A in the article by Pellagatti et al that begins on page 1225.