SRSF2 mutations in primary myelofibrosis: significant clustering with IDH mutations and independent association with inferior overall and leukemia-free survival.

Among spliceosome component mutations, those involving SF3B1 are most frequent in myelodysplastic syndromes with ring sideroblasts (MDS-RS; ∼ 75% incidence) and SRSF2 in chronic myelomonocytic leukemia (∼ 28% incidence). We recently reported on the lack of prognostic significance for SF3B1 mutations in both MDS-RS and primary myelofibrosis (PMF). In the current study, we examined the prevalence and prognostic relevance of SRSF2 mutations in PMF. Among 187 patients screened, 32 (17%) harbored SRSF2 monoallelic mutations affecting residue P95. Significant associations were demonstrated between SRSF2 mutations and advanced age (P < .01), IDH mutations (P < .01), and higher DIPSS-plus risk category (P = .03). SRSF2 mutations were associated with shortened overall (P < .01) and leukemia-free (P < .01) survival; the adverse effect on survival was independent of DIPSS-plus (P = .01; HR = 1.9; 95% CI, 1.1-3.0) and IDH mutations (P < .01; HR = 2.3; 95% CI, 1.4-3.8). In conclusion, SRSF2 mutations are relatively common in PMF, cluster with IDH mutations, and are independently predictive of poor outcome.

[1]  M. Gönen,et al.  Genetic analysis of patients with leukemic transformation of myeloproliferative neoplasms shows recurrent SRSF2 mutations that are associated with adverse outcome. , 2012, Blood.

[2]  A. Tefferi,et al.  SF3B1 mutations in primary myelofibrosis: clinical, histopathology and genetic correlates among 155 patients , 2012, Leukemia.

[3]  Michael Heuser,et al.  Frequency and prognostic impact of mutations in SRSF2, U2AF1, and ZRSR2 in patients with myelodysplastic syndromes. , 2012, Blood.

[4]  Claude Preudhomme,et al.  Mutations affecting mRNA splicing define distinct clinical phenotypes and correlate with patient outcome in myelodysplastic syndromes. , 2012, Blood.

[5]  A. Jankowska,et al.  Mutations in the spliceosome machinery, a novel and ubiquitous pathway in leukemogenesis. , 2012, Blood.

[6]  Franco Locatelli,et al.  Spliceosomal gene aberrations are rare, coexist with oncogenic mutations, and are unlikely to exert a driver effect in childhood MDS and JMML. , 2012, Blood.

[7]  E. Giné,et al.  Exome sequencing identifies recurrent mutations of the splicing factor SF3B1 gene in chronic lymphocytic leukemia , 2011, Nature Genetics.

[8]  A. Tefferi,et al.  IDH mutations in primary myelofibrosis predict leukemic transformation and shortened survival: clinical evidence for leukemogenic collaboration with JAK2V617F , 2011, Leukemia.

[9]  A. Tefferi,et al.  One thousand patients with primary myelofibrosis: the mayo clinic experience. , 2012, Mayo Clinic proceedings.

[10]  A. Sivachenko,et al.  SF3B1 and other novel cancer genes in chronic lymphocytic leukemia. , 2011, The New England journal of medicine.

[11]  P. Guglielmelli,et al.  Prognostic Impact of EZH2 and ASXL1 Mutation in Myelofibrosis , 2011 .

[12]  P. Guglielmelli,et al.  EZH2 mutational status predicts poor survival in myelofibrosis. , 2011, Blood.

[13]  A. Tefferi,et al.  Predictors of greater than 80% 2-year mortality in primary myelofibrosis: a Mayo Clinic study of 884 karyotypically annotated patients. , 2011, Blood.

[14]  M. Stratton,et al.  Somatic SF3B1 mutation in myelodysplasia with ring sideroblasts. , 2011, The New England journal of medicine.

[15]  S. Sugano,et al.  Frequent pathway mutations of splicing machinery in myelodysplasia , 2011, Nature.

[16]  P. Guglielmelli,et al.  Primary myelofibrosis with or without mutant MPL: comparison of survival and clinical features involving 603 patients , 2011, Leukemia.

[17]  F. Passamonti,et al.  DIPSS plus: a refined Dynamic International Prognostic Scoring System for primary myelofibrosis that incorporates prognostic information from karyotype, platelet count, and transfusion status. , 2011, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[18]  D. Gilliland,et al.  IDH1 and IDH2 mutation studies in 1473 patients with chronic-, fibrotic- or blast-phase essential thrombocythemia, polycythemia vera or myelofibrosis , 2010, Leukemia.

[19]  M. Cazzola,et al.  A dynamic prognostic model to predict survival in primary myelofibrosis: a study by the IWG-MRT (International Working Group for Myeloproliferative Neoplasms Research and Treatment). , 2010, Blood.

[20]  C. Bloomfield,et al.  The 2008 revision of the World Health Organization (WHO) classification of myeloid neoplasms and acute leukemia: rationale and important changes. , 2009, Blood.

[21]  D. Gilliland,et al.  TET2 mutations and their clinical correlates in polycythemia vera, essential thrombocythemia and myelofibrosis , 2009, Leukemia.

[22]  R. Mesa,et al.  Low JAK2V617F allele burden in primary myelofibrosis, compared to either a higher allele burden or unmutated status, is associated with inferior overall and leukemia-free survival , 2008, Leukemia.

[23]  D. Gilliland,et al.  MPL515 mutations in myeloproliferative and other myeloid disorders: a study of 1182 patients. , 2006, Blood.