Aberrant splicing in neuroblastoma generates RNA-fusion transcripts and provides vulnerability to spliceosome inhibitors

Despite extensive sequencing efforts, the number of identified recurrent mutations remain low in pediatric neuroblastoma. Researchers at Karolinska Institutet have now identified a large cohort of splicing dependent RNA-fusion transcripts in neuroblastoma, which could represent an alternative source for novel and potentially oncogenic gene products. They also show that neuroblastoma cells exhibit a selective vulnerability to spliceosome inhibition.

Neuroblastoma arises within the sympathetic nervous system and is the most frequent extracranial solid childhood cancer, exhibiting a high degree of clinical heterogeneity ranging from spontaneous regression to fatal progression despite intense clinical intervention. “The paucity of identified recurrent mutations hampers our understanding of disease mechanisms and translates into a lack of therapeutic targets” says Johan Holmberg and Yao Shi the corresponding authors of the article now published in Nucleic Acids Research.
Through analysis of a large cohort of sequenced neuroblastoma tumor samples, Johan Holmberg's lab have identified >900 RNA-fusion transcripts.

Notably, the majority of identified fusion transcripts were not products of chromosomal translocations but consisted of transcripts from genes in close genomic proximity, flanked by canonical splice sites. Furthermore, treatment with spliceosome inhibitors specifically targeted fusion transcripts but not their wild type cognates and selectively induced cell death in neuroblastoma cells.

They could also show that elevated expression of splicing factors is a strong predictor of poor clinical outcome and that in a mouse xenograft model of neuroblastoma, treatment with spliceosome inhibitors significantly impeded tumor growth. Taken together, their study suggests that splicing-dependent RNA-fusions represent an alternative mechanism, distinct from amino acid changing mutations, through which altered gene products with an oncogenic potential can be generated in neuroblastoma and that the spliceosome represents a possible targetable aspect of this disease.

The study was supported by the Swedish Children Cancer Foundation, the Swedish Cancer Society, Knut and Alice Wallenberg Foundation, Swedish Research Council (Vetenskapsrådet), The Strategic Research Programme in Cancer (StratCan, SFO) and the Swedish Brain Foundation.

Publication

Aberrant splicing in neuroblastoma generates RNA-fusion transcripts and provides vulnerability to spliceosome inhibitors.
Shi Y, Yuan J, Rraklli V, Maxymovitz E, Cipullo M, Liu M, Li S, Westerlund I, Bedoya-Reina OC, Bullova P, Rorbach J, Juhlin CC, Stenman A, Larsson C, Kogner P, O'Sullivan MJ, Schlisio S, Holmberg J
Nucleic Acids Res 2021 Feb;():