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M.A. Bauer et al.
aberrant splicing was of particular interest.34,42 Patients that have the less aggressive t(11;14) and have high novel splic- ing had no change in their OS. In the t(4;14) with high novel splicing (top 20%), the OS is significantly poorer, suggesting that there is an ultra-high risk group of t(4;14) with increased alternative splicing which showed some association with high-risk features such as LOH and dou- ble-hit. However, in the case of OS, it was the increased splicing which was the most significant. Although increased splicing is not exclusively associated with aggressive disease, these results provide evidence that changes to a cell's splicing as either a mechanism or result of other adverse features may suggest a more aggressive phenotype that may need to be treated differently.11
We showed that alternative splicing might be a signifi- cant mechanism that has pathogenic relevance to MM. Hotspot mutations in the driver gene, SF3B1, result in a sig- nificant impact on the MM transcriptome. Although SF3B1 mutations represent a small percentage of driver mutations, it does present a promising target for splice modulating drugs. In addition to the hotspot SF3B1 mutations, we also show a general increase in novel splicing in MM, and at its extreme, this is strongly associated with decreased PFS and OS. There are a number of spliceosome modulators under investigation including spliceostatins A-G, E7107 and H3B-8800, that target SF3B1.43,44 Recent work has shown that these compounds are more effective in cells that have higher expression of SF3B1 and are, there- fore, more dependent on SF3B1.45 Our observation of increased SF3B1 expression in the high splice group, which constitutes up to 20% of patients, may increase the number
of patients that may benefit from spliceosome modulators, rather than just the patients who have mutated SF3B1.
The results of the study make it clear that only looking at gene, or even transcript expression, can obscure impor- tant changes in the transcriptome. Alternative splicing may be an important pathogenic disease mechanism in MM that affects a wide range of important pathways. Additional studies of the MM transcriptome may provide important insights into the disease pathogenesis.
Disclosures
Celgene Corporation: Employment, Equity Ownership: MO, EF, AT.
Contributions
MB performed research; MB, CA and CW performed data analysis; MB took the lead in writing the manuscript; CA, CW, EB, MO, EF, AT, GM, BW provided critical feedback and helped shape the research, analysis and manuscript; BW super- vised the study.
Acknowledgments
Funding support for the CoMMpass dataset was provided by the Myeloma Genome Project. The CoMMpass dataset was generated by the Multiple Myeloma Research Foundation in col- laboration with the Multiple Myeloma Research Consortium.
Funding
Funding for data processing and storage was provided by Celgene Corporation. Other authors declare no competing inter- ests.
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