Hirabayashi S, Flotho C, Moetter J, Heuser M, Hasle H, Gruhn B, Klingebiel T, Thol F, Schlegelberger B, Baumann I, Strahm B, Stary J, Locatelli F, Zecca M, Bergstraesser E, Dworzak M, Van den Heuvel-Eibrink MM, De Moerloose B, Ogawa S, Niemeyer CM, Wlodarski MW, European working group of MDSiC. Such E, Cervera J, Costa D, Sole F, Vallespi T, Luno E, Collado R, Calasanz MJ, Hernandez-Rivas JM, Cigudosa JC, Nomdedeu B, Mallo M, Carbonell F, Bueno J, Ardanaz MT, Ramos F, Tormo M, Sancho-Tello R, del Canizo C, Gomez V, Marco V, Xicoy B, Bonanad S, Pedro C, Bernal T, Sanz GF. 2012;120(15):3080–8. 2008;15(8):819–26. SRSF2 mutation was detected in 34 (14.6%) of the 233 patients (supplemental Figure 1, available on the Blood Web site; see the Supplemental Materials link at the top of the online article). A variety of small molecules including ruxolitinib, enasidenib, midostaurin, and AG-120 are in clinical applications and/or late-stage clinical development [13,14,15,16,17,18,19,20,21]. This review focuses on the incidence of mutant SRSF2 across various MMOS as well as recent clinical development of spliceosome inhibitors. For example, Schnittger et al reported that no survival impact was observed in their larger CMML cohort41 ; Makishima et al also reported that SRSF2 mutations did not affect outcomes in CMML patients.10 Further analyses on larger patient cohorts are needed to confirm these findings. Recurrent somatic mutation of SRSF2, one of the RNA splicing machinery genes, has been identified in a substantial proportion of patients with myelodysplastic syndrome (MDS). To understand the consequences and effects of SRSF2P95H mutation on normal haematopoiesis, several groups, including our lab, have generated in vivo mouse models using various gene targeting strategies and Cre recombinases. 2016;91(5):492–8. 2016;374(23):2209–21. 2016;9(1):67. Additional factors that negatively influenced OS as per multivariate analyses were older age (> 65 years, p = 0.04), WBC > 15 × 109/L (p < 0.0001), presence of anemia (hemoglobin < 10 g/dL in women and < 11 g/dL in men; p = 0.0002), thrombocytopenia (< 100 × 109/L; p < 0.0001) and an absolute lymphocyte count (ALC) > 4 × 109/L (p = 0.03) [27, 56]. Phase 1/2 study of pacritinib, a next generation JAK2/FLT3 inhibitor, in myelofibrosis or other myeloid malignancies. The mutation was more frequently detected in patients with chronic myelomonocytic leukemia (CMML) than in other FAB subtypes (P = .025; Table 1). SRSF2 has a RNA recognition motif and thus promotes spliceosome assembly at adjacent splice sites to allow appropriate exon inclusion [28, 33, 34]. cells) were significantly associated with SRSF2 mutations in a study done on MDS/MPN entities. These mutations are being used as biomarkers for classification and druggable targets [9,10,11,12]. Mapping of the MDS and MDS/MPN genome identified recurrent heterozygous mutations in the RNA splicing machinery, with the SF3B1, SRSF2, and U2AF1 genes being frequently mutated. To the best of our knowledge, this is the first report to show a close association of SRSF2 mutation with RUNX1, IDH2, and ASXL1 mutations in MDS and the stability of this mutation during the clinical follow-ups. Blood. Komeno Y, Huang YJ, Qiu J, Lin L, Xu Y, Zhou Y, Chen L, Monterroza DD, Li H, DeKelver RC, Yan M, Fu XD, Zhang DE. The myelodysplastic/myeloproliferative neoplasms: myeloproliferative diseases with dysplastic features. SRSF2 is comparatively less common (2–9%) and is mostly present in association with other mutations in genotypes carrying high mutation burden [71]. Genomic aberrations have been reported at a frequency as high as 75% along with multiple somatic mutations [23]. Clinical manifestation of the SRSF2 gene mutation in Chinese patients with chronic myelomonocytic leukemia. EZH2, RUNX1, BCOR, IKAROS and CASP8, etc.) Blood. In two other studies, only 1/76 patients with JMML carried a SRSF2 mutation [26, 65]. Nature. Part of One patient with MDS, unclassifiable, by WHO classification was excluded from the statistical analysis. Patnaik MM, Lasho TL, Finke CM, Hanson CA, Hodnefield JM, Knudson RA, Ketterling RP, Pardanani A, Tefferi A. Spliceosome mutations involving SRSF2, SF3B1, and U2AF35 in chronic myelomonocytic leukemia: prevalence, clinical correlates, and prognostic relevance. The SR protein family of splicing factors: master regulators of gene expression. Frequent pathway mutations of splicing machinery in myelodysplasia. It is stable during the clinical course and may play little role in disease progression. This interesting finding is worthy of further confirmation by studies on more patients. Xiao et al demonstrated that SRSF2 is essential for genomic stability in their SRSF2-knockout mouse model.40 Because mutation of SRSF2 is supposed to result in loss of its protein function, the frequent occurrence of additional gene mutations at diagnosis and acquisition of new mutations during follow-ups in patients with SRSF2 mutation in the current study support the claim that depletion of SRSF2 may lead to DNA hypermutability.40 Conversely, Schnittger et al reported that SRSF2 mutation were mutually exclusive with EZH2 mutation in CMML patients.41 In the current cohort, the same finding also was observed in patients with CMML, but not in those with other subtypes: all 10 CMML patients with SRSF2 mutation had wild-type EZH2 (data not shown). SRSF2, a component of RNA splicing machinery, is one of the most frequent mutations in MDS and CMML. Science. In addition to the common i(17q), these neoplasms had frequent mutations in SRSF2 (55%), SETBP1 (59%), ASXL1 (55%), and NRAS (31%); TET2 and TP53 mutations were rare. SRSF2 mutation was closely associated with male sex (P = .001) and older age (P < .001). 2016;127(20):2391–405. 2012;31(1):162–74. EMBO J. volume 6, Article number: 29 (2018) SRSF2 has been associated with worse survival outcomes in low-risk MDS patients and PMF [43, 44, 55] but evidence has not been very clear among MDS/MPN overlap syndromes. SRSF2 mutations were studied sequentially in 173 samples from 66 patients, including 8 patients with SRSF2 mutation and 58 patients without mutation at diagnosis. Department of Medicine, New York Medical College and Westchester Medical Center, Valhalla, NY, USA, Amandeep Aujla, Michael Karass & Delong Liu, Section of Hematology-Oncology, Department of Medicine, Baylor College of Medicine, Houston, TX, USA, Division of Blood and Marrow Transplantation, Department of Medicine, Stanford University, Stanford, CA, USA, The affiliated Cancer Hospital of Zhengzhou University and Henan Cancer Hospital, 127 Dongming Road, Zhengzhou, 450008, China, You can also search for this author in 2017;5:33. No survival differences were found between the patients with and without SRSF2 mutation in the higher risk groups (Figure 1C,E,G). 2008;22(7):1308–19. Clinical and biological implications of partial tandem duplication of the MLL gene in acute myeloid leukemia without chromosomal abnormalities at 11q23. Mortera-Blanco T, Dimitriou M, Woll PS, Karimi M, Elvarsdottir E, Conte S, Tobiasson M, Jansson M, Douagi I, Moarii M, Saft L, Papaemmanuil E, Jacobsen SEW, Hellstrom-Lindberg E. SF3B1-initiating mutations in MDS-RSs target lymphomyeloid hematopoietic stem cells. Subgroup analysis showed that the poor impact of SRSF2 mutation on OS was only demonstrated in the patients of lower risk groups defined either by IPSS (low and intermediate-1, 69.3 months vs 32.0 months, P = .002; Figure 1B), by World Health Organization classification (RA, RARS, refractory cytopenia with unilineage dysplasia, and refractory cytopenia with multilineage dysplasia, with or without ring sideroblasts, 93.0 months vs 28.7 months, P = .001; Figure 1D), or by FAB classification (RA and RARS, 87.4 months vs 28.7 months, P = .001; Figure 1F). The universal involvement of Pro95 in SRSF2 mutation indicates a critical role of this residue on the protein function, which needs to be explored by further studies. Spliceosomal gene mutations are frequent events in the diverse mutational spectrum of chronic myelomonocytic leukemia but largely absent in juvenile myelomonocytic leukemia. Hwang SM, Kim SY, Kim JA, Park H-S, Park SN, Im K, Kim K, Kim S-M, Lee DS. The splicing of pre-mRNA, a highly regulated cascade of processes, is important for gene expression and genetic diversity; more than 90% of human genes undergo alternative splicing to make various protein isoforms for different biologic functions.1,2 SRSF2, located at 17q25.1, encodes serine/arginine-rich splicing factor 2 that belongs to the serine/arginine-rich protein family, important for splice-site selection, spliceosome assembly, and both constitutive and alternative splicing.3 Recently, through next-generation whole exome sequencing, recurrent somatic mutations involving the RNA splicing machinery were identified in a substantial proportion of patients with myelodysplastic syndrome (MDS),4-7 a myeloid hematopoietic disorder characterized by ineffective hematopoiesis, cytopenias, and risk of transformation to acute leukemia.8,9 Among these mutations, the clinical relevance of 2 prevalent mutations, U2AF354,6,10 and SF3B1,4,5,7,11-14 have been explored. Kielkopf CL. Makishima H, Visconte V, Sakaguchi H, Jankowska AM, Abu Kar S, Jerez A, Przychodzen B, Bupathi M, Guinta K, Afable MG, Sekeres MA, Padgett RA, Tiu RV, Maciejewski JP. 2014;28(11):2206–12. Cancer Cell. With this analysis, the investigators examined the impact of SF3B1 mutations on R-loop formation in MDS and leukemia cells, as well as the impact of SF3B1 mutations on associated DNA damage response in MDS and leukemia cells. This review focuses on SRSF2 mutations across various entities of MMOS. 2.1.3. 2012;119(14):3203–10. Spliceosome mutations are observed in MDS, chronic lymphocytic leukemia (CLL), AML, and chronic myelomonocytic leukemia (CMML), and these mutations can cause abnormal expression patterns of some genes involved in cancer pathogenesis (PMID: 23327988). Genomic classification and prognosis in acute myeloid leukemia. 2002;99(3):840–9. Blood. Sun C, Zhang S, Qiao C, Yang X, Li J. Wang HY, Xu X, Ding JH, Bermingham JR Jr, Fu XD. However, the clinical and biologic characteristics of MDS with this mutation remain to be addressed. Further exploration showed that the prognostic impact of SRSF2 mutation might be attributed to its close association with old age. 2012;26(8):1879–81. A high frequency of SRSF2 mutations (40%) was reported among a cohort of 60 aCML [54] while its frequency has been reported variably in other studies [67, 69, 70]. SF3B1 gene mutation has been reported to have significant impact on OS in 2 studies,5,35 but not in others.11,13 The U2AF1 mutation did not show influence on OS in one study,6 whereas it was associated with shorter survival in another study.10 In the current study, SRSF2 mutation possessed negative impact on OS in MDS patients, especially for those with lower risk disease, similar to the finding of Makishima et al.10 However, we found that the SRSF2 mutation was not an independent poor prognostic factor, and its impact on OS might be a reflection of the close association of this mutation with old age.