Pathologic Spectrum and Molecular Landscape of Myeloid Disorders Harboring SF3B1 Mutations

Abstract

Objectives SF3B1 mutations are the most common mutations in myelodysplastic syndromes (MDS). The International Working Group for the Prognosis of MDS (IWG-PM) recently proposed SF3B1-mutant MDS (SF3B1-mut-MDS) as a distinct disease subtype. We evaluated the spectrum and molecular landscape of SF3B1-mutated myeloid disorders and assessed the prognostication in MDS harboring SF3B1 mutations (MDS-SF3B1). Methods Cases were selected by retrospective review. Clinical course and laboratory and clinical findings were collected by chart review. SF3B1-mut-MDS was classified following IWG-PM criteria. Results SF3B1 mutations were identified in 75 of 955 patients, encompassing a full spectrum of myeloid disorders. In MDS-SF3B1, Revised International Prognostic Scoring System (IPSS-R) score greater than 3 and transcription factor (TF) comutations were adverse prognostic markers by both univariate and multivariate analyses. We confirmed the favorable outcome of IWG-PM-defined SF3B1-mut-MDS. Interestingly, it did not show sharp prognostic differentiation within MDS-SF3B1. Conclusions SF3B1 mutations occur in the full spectrum of myeloid disorders. We independently validated the favorable prognostication of IWG-PM-defined SF3B1-mut-MDS. However it may not provide sharp prognostication within MDS-SF3B1 where IPSS-R and TF comutations were prognostic-informative. Larger cohort studies are warranted to verify these findings and refine MDS-SF3B1 prognostication.

SF3B1 mutated MDS: Blast count, genetic co-abnormalities and their impact on classification and prognosis

“…In this study, we evaluated the IWG-PM proposed SF3B1 entity criteria. We confirmed the favorable clinical outcome of SF3B1 entity similar to recently published studies [21,22]. Additionally, in line with Komrokji et al we observed a significantly longer OS of SF3B1 entity patients compared to SF3B1 non-entity patients, in contrast to Venable et al who did not observe significant differences in OS between SF3B1ent and SF3B1nent presumably due to the small cohort size [21].…”

“…SF3B1 mutations are frequently detected within MDS and associated with favorable prognosis [5][6][7]. In our WGS-based cohort of 734 MDS patients we identified 231/734 (31%) cases with SF3B1 mutations verifying known hotspots in K700, K666 and H662 [4,7,8,20,21] and confirming a heterozygous SF3B1 mutation status with high median VAFs (35%) across all entities. VAFs >30% were observed in 77% of SF3B1 mut samples.…”

SF3B1 mutations in AML are strongly associated with MECOM rearrangements and may be indicative of an MDS pre-phase

“…However, it might be unidentified in others. Alternatively, SF3B1 mut CHIP or CCUS (clonal cytopenia with undetermined significance) may represent relevant precursor lesions of SF3B1 mut AML, in line with Venable et al, showing that SF3B1 mut cases comprise the full pathologic spectrum of myeloid disorders from CCUS to AML [14]. In SF3B1 mut s-AML patients, we frequently detected MECOM-r and RUNX1 mutations, both known AML driver genes [5].…”

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

“…Indeed, MDS patients with a mutated SF3B1 genotype showed lower WT1 expression values than the WT counterpart. Because the expression of WT1 at normal levels is an indicator of a good prognosis, this result corroborates the role of SF3B1 status as a good prognosis marker [ 5 , 34 , 35 , 36 ].…”