SF3B1 Mutations Are Associated with Favorable Cytogenetics in Patients with Myelodysplastic Syndromes with Ring Sideroblasts

Somatic mutations of splicing factor 3B, subunit 1 (SF3B1) are prevalent in myelodysplastic syndromes (MDS) with ring sideroblasts (RS). Little is known about the clinical phenotype associated with these mutations. Initial studies have reported an excellent event-free survival (EFS) in patients with SF3B1 mutations but subsequent reports did not confirm that observation. Therefore, its clinical significance remains uncertain. Our objective was to determine if the SF3B1 mutational status predicts distinctive morphological, cytogenetic or clinical characteristics in patients with MDS with RS.

Twenty-seven patients diagnosed with MDS and ≥ 15% RS in bone marrow aspiration between 2000 and 2011 at our institution and other hospitals affiliated to the Quebec Leukemia Cell Bank (BCLQ) and with available material for genetic analyses were included in this study. Morphology of samples was revised. After DNA extraction, polymerase chain reaction was performed to amplify SF3B1 mutational hotspots in exons 13 to 15. Amplicons were sequenced by the Sanger method. Clinical and laboratory data were collected retrospectively from hospital medical records and BCLQ database.

Point mutations of SF3B1 were found in 48% (13/27) with the following distribution: refractory anemia with RS (RARS): 7/10, refractory cytopenia with multilineage dysplasia (RCMD): 5/10 and refractory anemia with excess blasts (RAEB): 1/7. All mutations were heterozygous nonsense mutations and K700E exon 15 mutations accounted for 85% (11/13) of mutations. The remaining mutations were located in exon 14 at position 666.

In the entire cohort, SF3B1 mutations were associated with an older median age at diagnosis (69 vs 60 years, p= 0.007). They were associated with favorable cytogenetics whereas unmutated SF3B1 was associated with unfavorable cytogenetics (8 cases vs 0 with favorable cytogenetics and 0 cases vs 11 with unfavorable cytogenetics for mutated and wild type SF3B1 respectively, p < 0.0001). Median overall survival (OS) was similar in the 2 groups (not reached vs 27 months, p=0.7) but median EFS was higher in patients with mutated SF3B1 (not reached vs 5 months, p=0.02).

To evaluate the influence of higher bone marrow blasts on outcomes, analyses were restricted to the RARS and RCMD-RS categories. In that subgroup, SF3B1 mutations were correlated with higher median platelet counts at diagnosis (201 vs 70 × 10⁹/L, p=0,04). In addition, SF3B1 mutations remained associated with favorable cytogenetics, and unmutated SF3B1 with unfavorable cytogenetics (p=0.004). Moreover, SF3B1 mutations were more frequently detected within favorable or intermediate-1 categories of the International Prognostic Scoring System (IPSS) compared to wild type SF3B1 (p=0.04). However, in patients with < 5% bone marrow blasts, EFS was similar between mutated and unmutated SF3B1 (not reached vs 46 months, p =0.4).

In this series, SF3B1 mutations are frequent in MDS with RS and they are strongly associated with favorable cytogenetics. They are mostly detected among low-risk groups of the World Health Organisation classification (RARS and RCMD-RS), but they are not independently associated with an increased overall or event-free survival.

No relevant conflicts of interest to declare.