SF3B1 mutations are prevalent in myelodysplastic syndromes with ring sideroblasts but do not hold independent prognostic value

Patnaik, Mrinal M.; Lasho, Terra L.; Hodnefield, Janice M.; Knudson, Ryan A.; Ketterling, Rhett P.; Garcia‐Manero, Guillermo; Steensma, David P.; Pardanani, Animesh; Hanson, Curtis A.; Tefferi, Ayalew

doi:10.1182/blood-2011-09-377994

Cited by 193 publications

(109 citation statements)

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“…In the current study, the mutational frequencies were SF3B1285%, JAK2V617F-33%, ASXL1-29%, DNMT3A-13%, SETBP1-13%, and TET2-10%. As in other myeloid neoplasms with RS, the presence of SF3B1 mutations strongly correlated with the BM RS%, and did not independently impact survival [5,13,14].…”

Section: Discussionmentioning

confidence: 48%

“…These variables were not found to be prognostic in our study. While the JAK2V617F mutation is associated with MPN-like features, SF3B1 mutations strongly correlate with the presence of BM RS, and both these mutations do not independently impact survival [5]. Based on our genomically integrated data, we provide a practical, mutationally enhanced prognostic model; with two points for an abnormal karyotype, one point for either ASXL1 and/or SETBP1 mutations, and one point for a HB < 10 gm/dl.…”

Section: Discussionmentioning

confidence: 99%

“…The advent of next-generation sequencing (NGS) has helped define the molecular landscape of patients with RARS-T. Common abnormalities include: spliceosome component mutations-SF3B1 90%, SRSF2 7%, U2AF1 5%, ZRSR2 3%; signal pathway mutations-JAK2V617F 57%, MPL 3%, CBL 4%; mutations in epigenetic regulator genes-ASXL1 15%, TET2 25%, EZH2 7%, DNMT3A 15%, IDH2 4%, and mutations involving transcription factors-ETV6 3%, RUNX1 1% [3,4]. Amongst these, SF3B1 mutations are the most frequent and strongly correlate with the presence of BM RS [5]. JAK2V617F mutations are second most common and contribute to the myeloproliferative phenotype.…”

Section: Introductionmentioning

confidence: 99%

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Predictors of survival in refractory anemia with ring sideroblasts and thrombocytosis (RARS‐T) and the role of next‐generation sequencing

et al. 2016

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Refractory anemia with ring sideroblasts and thrombocytosis (RARS-T) shares overlapping features of myelodysplastic syndromes (MDS) and myeloproliferative neoplasms (MPN). RARS-T is characterized by SF3B1 and JAK2 mutations and prognosis is considered to be better than MDS but not as good as MPN. The objective of the study was to identify predictors of survival in RARS-T. We analyzed clinical and laboratory variables in 82 patients and applied a 27-gene NGS assay to 48 marrow samples obtained at diagnosis. 94% of patients had 1 mutations; common mutations being: SF3B1 85%, JAK2V617F 33%, ASXL1 29%, DNMT3A 13%, SETBP1 13% and TET2 10%. In a multivariable survival analysis (n 5 82), anemia (P 5 0.02) [HB< 10 gm/dl: HR 2.3, 95% CI 1.2-4.6] and abnormal karyotype (P 5.01) [HR 6.1, 95% CI 2.7-13.8] were independently prognostic for inferior survival. In patients with NGS information (n 5 48), univariate analysis showed association between poor survival and presence of SETBP1 (P 5 0.04) or ASXL1 (P 5 0.08) mutations whereas the absence of these mutations (ASXL1wt/SETBP1wt) was favorable (P 5 0.04); the number of concurrent mutations did not provide additional prognostication (P 5 0.3). We developed a HR-weighted prognostic model, with 2 points for an abnormal karyotype, 1 point for either ASXL1 and/or SETBP1 mutations, and 1 point for a HB level < 10 gm/dl, which effectively stratified patients into three risk categories; low (0 points), intermediate (1 point) and high ( 2 points), with median survivals of 80, 42 and 11 months respectively (P 5 0.01). In summary, we confirm the unique mutational landscape in RARS-T and provide a novel mutationenhanced prognostic model.

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confidence: 48%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Predictors of survival in refractory anemia with ring sideroblasts and thrombocytosis (RARS‐T) and the role of next‐generation sequencing

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“…Mutations involving SF3B1 are common in MDS-RS ( 80%), and to a lesser extent in PMF (<10%), but hold no independent prognostic value [12,17,25]. These mutations have a strong phenotypic correlation with the presence of BM RS.…”

Section: Discussionmentioning

confidence: 99%

“…SF3B1 mutational analysis (SF3B1exons 13-15) was performed according to previously published methods [25]. For detection of SRSF2 and U2AF35 mutations, we applied standard PCR techniques and bidirectional sequencing.…”

Section: Methodsmentioning

confidence: 99%

Spliceosome mutations involving SRSF2, SF3B1, and U2AF35 in chronic myelomonocytic leukemia: Prevalence, clinical correlates, and prognostic relevance

Patnaik¹,

Lasho²,

Finke³

et al. 2013

American J Hematol

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SRSF2, SF3B1, and U2AF35 (U2AF1) are the three most frequent genes involved with spliceosome mutations in myeloid malignancies. SF3B1 mutations are most frequent (~80%) in myelodysplastic syndromes (MDS) with ring sideroblasts (RS) but lack prognostic relevance. SRSF2 mutations are associated with shortened overall (OS) and leukemia-free survival (LFS) in both MDS and myelofibrosis. In this study of 226 patients with chronic myelomonocytic leukemia (CMML), mutational frequencies were 40% for SRSF2 (all affecting P95), 6% for SF3B1 (primarily K700E) and 9% for U2AF35 (mostly S34F and Q157P/R). These mutations were mutually exclusive and 54% of the patients displayed at least one mutation. The three mutation groups were phenotypically similar, with the exception of higher RS% (P < 0.0001) in patients with SF3B1 mutations. At a median follow-up of 15 months, 176 (78%) deaths and 32 (14%) leukemic transformations were documented. OS (median survivals of 17, 16, 17, and 20 months; P 5 0.48) and LFS (leukemic transformation rates of 17, 13, 15, and 5%; P 5 0.63) were similar among patients with none of the three mutations, SRSF2, SF3B1, or U2AF35 mutations, respectively. We conclude that SRSF2 is the most frequently mutated spliceosome gene in CMML but neither it nor SF3B1 or U2AF35 mutations are prognostically relevant. Am. J. Hematol. 88:201-206, 2013. V C 2012 Wiley Periodicals, Inc. IntroductionChronic myelomonocytic leukemia (CMML) is a clonal hematopoietic stem cell disorder characterized by features overlapping between myelodysplastic syndromes (MDS) and myeloproliferative neoplasms (MPN). The 2008 World Health Organization (WHO) criteria for diagnosis of CMML include; persistent peripheral blood monocytosis >1 3 10(9)/L, absence of the BCR-ABL1 fusion, absence of rearrangements of the PDGFRA or PDGFRB genes, absence of 20% myeloblasts or promonocytes in the blood and bone marrow (BM), and presence of dysplasia in one or more myeloid lineages [1]. CMML is further subclassified into CMML-1 (<5% circulating blasts and <10% BM blasts) and CMML-2 (5-19% circulating blasts, 10-19% BM blasts, or when Auer rods are present irrespective of the blast count), with the median over-all survival (OS) being 20 and 15 months respectively [1,2].Genetic aberrations are common in CMML and tend to involve different cellular targets and epigenetic regulatory pathways. These include mutations involving; RUNX1 . Thus far, in CMML, loss-of-function mutations involving EZH2 and ASXL1 have been associated with poor outcomes [10,11]. The data with regard to the other mutations needs further elucidation.Mutations in genes of the splicing machinery, such as SF3B1 (splicing factor 3B, subunit 1), SRSF2 (serine/arginine-rich splicing factor 2) and U2AF35, also known as U2AF1 (U2 small nuclear RNA auxiliary factor) are common in patients with myeloid malignancies [12][13][14]. SF3B1 mutations have a high prevalence ( 80%) in MDS and ring sideroblasts (RS) and do not influence either OS or leukemiafree survival (LFS) [15,16]. Similarly, these...

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Molecular Genetics of Myelodysplastic Syndromes

Bejar

Steensma

2012

Encyclopedia of Life Sciences

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Myelodysplastic syndromes (MDS) are a group of clonal haematopoietic disorders characterised clinically by inefficient haematopoiesis, cytopenias of the peripheral blood and a risk of progression to acute myeloid leukaemia (AML). Molecularly, MDS can be associated with a wide range of acquired chromosomal abnormalities, epigenetic alterations and single gene mutations. These abnormalities affect diverse molecular pathways including ribonucleic acid (RNA) splicing machinery, epigenetic modifiers, haematopoietic transcription factors, receptor tyrosine kinase signalling, cell cycle regulation and apoptosis. The particular combination of somatic genetic lesions in any given patient will influence how their disease is manifested, and together with individual background germline genotype may explain much of the clinical heterogeneity associated with MDS. Here, the common genetic abnormalities that underlie MDS and how these abnormalities influence the development and progression of these disorders have been reviewed. Key Concepts: MDS represent a collection of disorders marked by abnormal, inefficient haematopoiesis, cytopenias of the peripheral blood and a predisposition for progression to AML. Like other haematopoietic malignancies, MDS arise from the clonal expansion of a single, abnormal haematopoietic cell. The abnormal MDS cells that maintain the disease have the ability to self‐renew and clonally expand because they have a selective growth advantage compared to their normal counterparts. Impaired haematopoietic differentiation in MDS can lead to cytopenias or to the production of terminally differentiated cells with abnormal function. A combination of somatic genetic abnormalities (acquired changes to the deoxyribonucleic acid (DNA) coding sequence), epigenetic abnormalities (heritable changes in gene expression) and marrow microenvironmental abnormalities contribute to the development and progression of MDS. Approximately, 50% of MDS cells have a chromosomal abnormality detectable by routine metaphase karyotype analysis. More than 75% of patients have acquired mutations in one or more genes known to be recurrently altered in MDS. Recurrent mutations in MDS implicate several molecular pathways in the development and progression of disease including; altered RNA splicing mechanisms, epigenetic changes in DNA methylation and histone modifications, activation of growth factor signalling cascades, impaired differentiation and abnormal regulation of cell cycle and apoptosis. Acquired mutations in several MDS genes have prognostic significance that is independent of clinically based prognostic scoring systems. Chromosomal abnormalities and mutations in some genes can predict response to specific therapies used to treat patients with MDS.

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SF3B1 mutations are prevalent in myelodysplastic syndromes with ring sideroblasts but do not hold independent prognostic value

Cited by 193 publications

References 17 publications

Predictors of survival in refractory anemia with ring sideroblasts and thrombocytosis (RARS‐T) and the role of next‐generation sequencing

Predictors of survival in refractory anemia with ring sideroblasts and thrombocytosis (RARS‐T) and the role of next‐generation sequencing

Spliceosome mutations involving SRSF2, SF3B1, and U2AF35 in chronic myelomonocytic leukemia: Prevalence, clinical correlates, and prognostic relevance

Molecular Genetics of Myelodysplastic Syndromes

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