SF3B1 mutation identifies a distinct subset of myelodysplastic syndrome with ring sideroblasts

Abstract

Key Points• In MDS with ring sideroblasts, SF3B1 mutation defines a homogeneous subgroup with isolated erythroid dysplasia and favorable prognosis.• MDS with ring sideroblasts and wild-type SF3B1 is mainly characterized by multilineage dysplasia and unfavorable prognosis.Refractory anemia with ring sideroblasts (RARS) is a myelodysplastic syndrome (MDS) characterized by isolated erythroid dysplasia and 15% or more bone marrow ring sideroblasts. Ring sideroblasts are found also in other MDS subtypes, such as refractory cytopenia with multilineage dysplasia and ring sideroblasts (RCMD-RS). A high prevalence of somatic mutations of SF3B1 was reported in these conditions. To identify mutation patterns that affect disease phenotype and clinical outcome, we performed a comprehensive mutation analysis in 293 patients with myeloid neoplasm and 1% or more ring sideroblasts. SF3B1 mutations were detected in 129 of 159 cases (81%) of RARS or RCMD-RS. Among other patients with ring sideroblasts, lower prevalence of SF3B1 mutations and higher prevalence of mutations in other splicing factor genes were observed (P < .001). In multivariable analyses, patients with SF3B1 mutations showed significantly better overall survival (hazard ratio [HR], .37; P 5 .003) and lower cumulative incidence of disease progression (HR 5 0.31; P 5 .018) compared with SF3B1-unmutated cases. The independent prognostic value of SF3B1 mutation was retained in MDS without excess blasts, as well as in sideroblastic categories (RARS and RCMD-RS). Among SF3B1-mutated patients, coexisting mutations in DNA methylation genes were associated with multilineage dysplasia (P 5 .015) but had no effect on clinical outcome. TP53 mutations were frequently detected in patients without SF3B1 mutation, and were associated with poor outcome. Thus, SF3B1 mutation identifies a distinct MDS subtype that is unlikely to develop detrimental subclonal mutations and is characterized by indolent clinical course and favorable outcome. (Blood. 2015;126(2):233-241)

Splicing-factor alterations in cancers

“…Alterations in alternative splicing events lead to the production of pro-tumorigenic isoforms that have been linked to various steps of tumorigenesis, including proliferation, apoptosis, invasion, metabolism, angiogenesis, DNA damage, or even drug resistance and immune response. Malcovati et al 2011Malcovati et al , 2015Papaemmanuil et al 2011Papaemmanuil et al , 2013Wang et al 2011;Yoshida et al 2011;Bejar et al 2012;Damm et al 2012;Makishima et al 2012;Patnaik et al 2012;Visconte et al 2012;Walter et al 2013;Shirai et Yoshida et al 2011;Bejar et al 2012;Damm et al 2012;Makishima et al 2012;Thol et al 2012;Papaemmanuil et al 2013 MDS Yoshida et al 2011;Bejar et al 2012;Damm et al 2012;Graubert et al 2012;…”

Clinical Implications of Genetic Mutations in Myelodysplastic Syndrome

“…8,11,12 SF3B1 was the first spliceosome family member to be implicated, and is mutated in up to 80% of MDS cases with ringed sideroblasts. 6,15 Splicing factor mutations are heterozygous and generally mutually exclusive of one another, suggesting that cells cannot tolerate two mutations or, alternatively, that these changes have a redundant role in disease pathogenesis. The spliceosome functions to mediate intron excision and exon ligation in the generation of mature messenger RNA molecules.…”

Splicing factor mutations in MDS RARS and MDS/MPN-RS-T

“…Clonal analysis based on the variant allele frequency of SF3B1 and other co-existing mutations revealed that mutations in SF3B1 are present in the dominant clone in most cases. Interestingly, the percentage of BM RS is highly correlated with SF3B1 mutant allele burden [4,[6][7][8], which strongly suggests that mutant SF3B1 directly or indirectly contributes to the formation of RS. In fact, SF3B1 mutations have a high positive predictive value for disease phenotype with RS of 97.7%, whereas the absence of these mutations has an equivalent negative prediction value [7].…”

“…For example, Malcovati et al studied the influence of SF3B1 mutations on outcome in 293 patients with myeloid neoplasms with 1% or more RS [6]. In this cohort, SF3B1 mutations were detected in 129 of 159 patients (81%) with RARS or RCMD-RS, and multivariate analysis demonstrated that patients with SF3B1 mutations had significantly better overall survival [hazard ratio (HR) 0.37] and lower cumulative incidence of disease progression (HR 0.31).…”