Clinical significance of SF3B1 mutations in myelodysplastic syndromes and myelodysplastic/myeloproliferative neoplasms

In a previous study, we identified somatic mutations of SF3B1, a gene encoding a core component of RNA splicing machinery, in patients with myelodysplastic syndrome (MDS). Here, we define the clinical significance of these mutations in MDS and myelodysplastic/myeloproliferative neoplasms (MDS/MPN). The coding exons of SF3B1 were screened using massively parallel pyrosequencing in patients with MDS, MDS/MPN, or acute myeloid leukemia (AML) evolving from MDS. Somatic mutations of SF3B1 were found in 150 of 533 (28.1%) patients with MDS, 16 of 83 (19.3%) with MDS/MPN, and 2 of 38 (5.3%) with AML. There was a significant association of SF3B1 mutations with the presence of ring sideroblasts (P < .001) and of mutant allele burden with their proportion (P = .002). The mutant gene had a positive predictive value for ring sideroblasts of 97.7% (95% confidence interval, 93.5%-99.5%). In multivariate analysis including established risk factors, SF3B1 mutations were found to be independently associated with better overall survival (hazard ratio = 0.15, P = .025) and lower risk of evolution into AML (hazard ratio = 0.33, P = .049). The close association between SF3B1 mutations and disease phenotype with ring sideroblasts across MDS and MDS/MPN is consistent with a causal relationship. Furthermore, SF3B1 mutations are independent predictors of favorable clinical outcome, and their incorporation into stratification systems might improve risk assessment in MDS.

[1]  H. Akaike.  A new look at the statistical model identification , 1974 .

[2]  D. Catovsky,et al.  Chronic Myelomonocytic Leukaemia , 1975, British journal of haematology.

[3]  M Stefanelli,et al.  Estimation of Ferrokinetic Parameters by a Mathematical Model in Patients with Primary Acquired Sideroblastic Anaemia , 1978, British journal of haematology.

[4]  C. Berzuini,et al.  Quantitative evaluation of erythropoietic activity in dysmyelopoietic syndromes , 1982, British journal of haematology.

[5]  M. Cazzola,et al.  Natural history of idiopathic refractory sideroblastic anemia , 1988 .

[6]  T Hamblin,et al.  International scoring system for evaluating prognosis in myelodysplastic syndromes. , 1997, Blood.

[7]  N. Harris,et al.  The World Health Organization (WHO) classification of the myeloid neoplasms. , 2002, Blood.

[8]  M. Cazzola,et al.  Mitochondrial ferritin expression in erythroid cells from patients with sideroblastic anemia. , 2003, Blood.

[9]  M. Cazzola,et al.  Flow Cytometry Evaluation of Erythroid Dysplasia in Patients with Myelodysplastic Syndrome. , 2004 .

[10]  M. Cazzola,et al.  Aberrant mitochondrial iron distribution and maturation arrest characterize early erythroid precursors in low-risk myelodysplastic syndromes. , 2005, Blood.

[11]  M. Cazzola,et al.  Myelodysplastic syndromes--coping with ineffective hematopoiesis. , 2005, The New England journal of medicine.

[12]  Luca Malcovati,et al.  Prognostic factors and life expectancy in myelodysplastic syndromes classified according to WHO criteria: a basis for clinical decision making. , 2005, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[13]  M. Cazzola,et al.  Flow cytometry evaluation of erythroid dysplasia in patients with myelodysplastic syndrome , 2006, Leukemia.

[14]  Li Wang,et al.  Gene expression profiles of CD34+ cells in myelodysplastic syndromes: involvement of interferon-stimulated genes and correlation to FAB subtype and karyotype. , 2006, Blood.

[15]  M. Cazzola,et al.  Gene expression profiling of CD34+ cells in patients with the 5q− syndrome , 2007, British journal of haematology.

[16]  Thomas H Müller,et al.  New insights into the prognostic impact of the karyotype in MDS and correlation with subtypes: evidence from a core dataset of 2124 patients. , 2007, Blood.

[17]  M. Cazzola,et al.  Time-dependent prognostic scoring system for predicting survival and leukemic evolution in myelodysplastic syndromes. , 2007, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[18]  M. Cazzola,et al.  Haploinsufficiency of RPS14 in 5q− syndrome is associated with deregulation of ribosomal- and translation-related genes , 2008, British journal of haematology.

[19]  B. Bain,et al.  Diagnosis and classification of myelodysplastic syndrome: International Working Group on Morphology of myelodysplastic syndrome (IWGM-MDS) consensus proposals for the definition and enumeration of myeloblasts and ring sideroblasts , 2008, Haematologica.

[20]  T. Golub,et al.  Identification of RPS14 as a 5q- syndrome gene by RNA interference screen , 2007, Nature.

[21]  U. Germing,et al.  The myelodysplastic/myeloproliferative neoplasms: myeloproliferative diseases with dysplastic features , 2008, Leukemia.

[22]  Luca Malcovati,et al.  The Role of the Iron Transporter ABCB7 in Refractory Anemia with Ring Sideroblasts , 2008, PloS one.

[23]  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.

[24]  D. Birnbaum,et al.  TET2 mutation is an independent favorable prognostic factor in myelodysplastic syndromes (MDSs). , 2009, Blood.

[25]  M. Cazzola,et al.  Molecular and clinical features of refractory anemia with ringed sideroblasts associated with marked thrombocytosis. , 2009, Blood.

[26]  A. Hagemeijer,et al.  Acquired mutations in TET2 are common in myelodysplastic syndromes , 2009, Nature Genetics.

[27]  C. Mullighan.  TET2 mutations in myelodysplasia and myeloid malignancies , 2009, Nature Genetics.

[28]  R. Levine,et al.  Mutation in TET2 in myeloid cancers. , 2009, The New England journal of medicine.

[29]  A. Warren,et al.  A p53-dependent mechanism underlies macrocytic anemia in a mouse model of human 5q− syndrome , 2009, Nature Medicine.

[30]  S. Pileri,et al.  Induction of p53 and up-regulation of the p53 pathway in the human 5q- syndrome. , 2010, Blood.

[31]  G. Mufti,et al.  Next-generation sequencing of the TET2 gene in 355 MDS and CMML patients reveals low-abundance mutant clones with early origins, but indicates no definite prognostic value. , 2010, Blood.

[32]  Ryan D. Morin,et al.  Identification of miR-145 and miR-146a as mediators of the 5q– syndrome phenotype , 2010, Nature Medicine.

[33]  M. Cazzola,et al.  Ring sideroblasts and sideroblastic anemias , 2011, Haematologica.

[34]  M. Cazzola,et al.  Impact of the degree of anemia on the outcome of patients with myelodysplastic syndrome and its integration into the WHO classification-based Prognostic Scoring System (WPSS) , 2011, Haematologica.

[35]  D. Neuberg,et al.  Clinical effect of point mutations in myelodysplastic syndromes. , 2011, The New England journal of medicine.

[36]  R. Levine,et al.  Molecular biology of myelodysplastic syndromes. , 2011, Seminars in oncology.

[37]  M. Cazzola,et al.  Myelodysplastic/myeloproliferative neoplasms. , 2011, Hematology. American Society of Hematology. Education Program.

[38]  Benjamin L Ebert,et al.  Unraveling the molecular pathophysiology of myelodysplastic syndromes. , 2011, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[39]  M. L. Le Beau,et al.  The dawn of the molecular era of the myelodysplastic syndromes. , 2011, The New England journal of medicine.

[40]  M. Cazzola,et al.  Classification and prognostic evaluation of myelodysplastic syndromes. , 2011, Seminars in oncology.

[41]  M. Cazzola,et al.  Deep sequencing reveals double mutations in cis of MPL exon 10 in myeloproliferative neoplasms , 2011, Haematologica.

[42]  Frequent Pathway Mutations of Splicing Machinery in Myelodysplasia , 2011 .

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

[44]  L. Malcovati.  I-009 RARS-T: Molecular and clinical features of refractory anemia with ringed sideroblasts associated with marked thrombocytosis , 2013 .

[45]  H. Kantarjian,et al.  Myelodysplastic/Myeloproliferative Neoplasms, Unclassifiable (MDS/MPN, U): Natural History and Clinical Outcome By Therapeutic Approach , 2013 .