Background And Aims

The 2016 revised WHO classification incorporated somatic mutation in SF3B1 spliceosome gene within the diagnostic criteria of myelodysplastic syndrome (MDS) with ring sideroblasts (RS). However, SF3B1^wt MDS-RS display significantly different clinical features and outcome from those of SF3B1^mut MDS-RS. Recently, the recognition of SF3B1-mutant MDS as a distinct nosologic entity has been proposed to overcome this limitation.

Methods

To further validate this proposal, we studied a cohort of 124 MDS patients by whole transcriptome analysis of CD34+ bone marrow mononuclear cells and explored differential gene expression according to morphology and molecular genetics. We restricted our analysis to MDS with bone marrow blasts below 5% and investigated MDS with RS >5% (cases) or MDS negative for both splicing mutation and RS (controls).

Results

SF3B1 mutation was found to be mutually exclusive with SRSF2 and TP53 mutations (q-value <0.05). Therefore, the study population was divided into three categories, MDS-RS-SF3B1^mut (n=64), MDS-RS-SF3B1^wt (n=25) and MDS-SLD/MLD (n=35).

We identified 1566 differentially expressed genes (DEG) between MDS-RS-SF3B1^mut and MDS-RS-SF3B1^wt and confirmed that ABCB7 downregulation is associated with SF3B1 mutation and not RS phenotype per se (Figure 1AB).

Finally, we identified two clusters of DEG in MDS-RS-SF3B1^mut and MDS-RS-SF3B1^wt. K-means clustering analysis recognized MDS-RS-SF3B1^mut from other subgroups with 81.1% accuracy. MDS-RS-SF3B1^mut exhibited a specific downregulation of cellular adhesion and an upregulation of G-alpha signaling molecules (adjusted p-value < 0.01, Figure 2).

Conclusions

Overall, this study contributes to unveil molecular features of SF3B1-mutant MDS and provides further evidence to support recognition of somatic SF3B1 mutation as a disease-defining genetic lesion.