Only SF3B1 mutation involving K700E independently predicts overall survival in myelodysplastic syndromes

Abstract

Background SF3B1 mutations (SF3B1mut) in myelodysplastic syndromes (MDS) frequently involve codon K700E and have a favorable prognosis. The prognostic effect of non‐K700E SF3B1mut is uncertain. Methods The authors analyzed the clinicopathological features and outcomes of a single‐institution series of 94 treatment‐naive SF3B1mut MDS patients (18%) and 415 treatment‐naive SF3B1wt MDS patients and explored the differences between K700E and non‐K700E SF3B1mut MDS. Results Fifty‐five patients (59%) carried K700E. Recurrent non‐K700E mutations (39 [41%]) included R625, H662, and K666. Compared with SF3B1mut K700E patients, non‐K700E patients had a lower median absolute neutrophil count (1.8 vs 2.4; P = .005) and were frequently “high” according to the Revised International Prognostic Scoring System (19% vs 4%; P = .031). Non‐K700E MDS was associated frequently with RUNX1 (26% vs 7%; P = .012) and exclusively with BCOR, IDH2, and SRSF2 mutations. A splicing analysis showed the differential distribution of alternatively spliced events and gene expression profiles between K700 and non‐K700E MDS patients. The majority (at least 80%) of SF3B1mut K700E, SF3B1mut non‐K700E, and SF3B1wt patients were treated with hypomethylating agents. Over a median follow‐up of 16 months, SF3B1mut had superior overall survival (OS) in comparison with SF3B1wt in all MDS patients (not reached vs 25.2 months; P = .0003), in patients with low‐grade MDS, and in patients with myelodysplastic syndromes with ring sideroblasts (MDS‐RS). Compared with SF3B1wt, SF3B1mut K700E had superior outcomes in all MDS (median OS, 25 months vs not reached; P = .0001), in low‐grade MDS (median OS, 41.3 months vs not reached; P = .0015), and in MDS‐RS (median OS, 22.3 months vs not reached; P = .0001), but no significant difference was seen between non‐K700E and SF3B1wt MDS. By multivariable analysis, the absence of SF3B1mut K700E mutations was independently associated with the prognosis. Conclusions This study highlights the importance of the SF3B1 mutation subtype in MDS risk assessment. Lay Summary Myelodysplastic syndromes (MDS) with SF3B1 mutations are regarded as having a favorable prognosis by both the World Health Organization and the International Working Group for the Prognosis of Myelodysplastic Syndromes. However, this article shows that only MDS patients with SF3B1 K700E mutations have a favorable prognosis (and not MDS patients with SF3B1 mutations involving other codons). This has important implications for refining future MDS subclassification and risk assessment criteria.

A Novel Prognostic Scoring Model for Myelodysplastic Syndrome Patients With SF3B1 Mutation

“…The majority were categorized into good karyotype risk group and lower risk group according to IPSS-R. K700E was the most common mutation site of SF3B1 in our study. But the patients with K700E had no survival advantage over the patients without K700E, which was inconsistent with the results from Rashmi KS, et al showing that SF3B1 mutated MDS with K700E had a remarkably better OS in contrast to non-K700E mutations (25).…”

“…But the patients with K700E had no survival advantage over the patients without K700E, which was inconsistent with the results from Rashmi KS, et al. showing that SF3B1 mutated MDS with K700E had a remarkably better OS in contrast to non-K700E mutations ( 25 ).…”

Patient-specific MDS-RS iPSCs define the mis-spliced transcript repertoire and chromatin landscape of SF3B1-mutant HSPCs

“…In addition, the specificity of the mutant SF3B1 signature, derived from the iPSC lines and validated in primary patient samples, identifies atypical mutations involving the K700 hotspot, such as the SF3B1p.K700_V701delKV that we report here, as functionally equivalent to the K700E mutation, and can thus be further used to evaluate the role of putative pathogenic variants in SF3B1 . 45 …”

Detection of SF3B1 p.Lys700Glu Mutation by PNA-PCR Clamping in Myelodysplastic Syndromes and Myeloproliferative Neoplasms

“…By contrast, Dalton et al report that the p.Lys666Asn hotspot is associated with MDS with excess blasts and increased progression to acute myeloid leukemia [ 31 ]. More recently, Kanagal-Shamanna et al found that only the p.Lys700Glu mutation independently predicts better overall survival in MDS, suggesting that the identification of this SF3B1 mutation type is important for risk stratification [ 32 ]. In this paper, we demonstrated the feasibility and utility of the PNA-PCR clamping approach in the identification of the most frequent SF3B1 mutations.…”