Search

Splicing modulation is a promising treatment strategy pursued to date only in splicing factor-mutant cancers; however, its therapeutic potential is poorly understood outside of this context. Like splicing factors, genes encoding components of the cohesin complex are frequently mutated in cancer, including myelodysplastic syndromes (MDS) and secondary acute myeloid leukemia (AML), where they are associated with poor outcomes. Here, we showed that cohesin mutations are biomarkers of sensitivity to drugs targeting the splicing factor 3B subunit 1 (SF3B1) H3B-8800 and E-7107. We identified drug-induced alterations in splicing, and corresponding reduced gene expression, of a number of DNA repair genes, including BRCA1 and BRCA2, as the mechanism underlying this sensitivity in cell line models, primary patient samples and patient-derived xenograft (PDX) models of AML. We found that DNA damage repair genes are particularly sensitive to exon skipping induced by SF3B1 modulators due to their long length and large number of exons per transcript. Furthermore, we demonstrated that treatment of cohesin-mutant cells with SF3B1 modulators not only resulted in impaired DNA damage response and accumulation of DNA damage, but it sensitized cells to subsequent killing by poly(ADP-ribose) polymerase (PARP) inhibitors and chemotherapy and led to improved overall survival of PDX models of cohesin-mutant AML in vivo. Our findings expand the potential therapeutic benefits of SF3B1 splicing modulators to include cohesin-mutant MDS and AML. Editor's summary: Splicing modulators have been developed to treat cancers with splicing factor mutations, such as myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). Mutations in the cohesin complex are also very common in MDS and AML, but whether these cohesin-mutant cancers would respond to splicing modulation is unknown. Here, Wheeler and colleagues showed that cohesin-mutant cells were particularly sensitive to splicing modulators, which induced mis-splicing and down-regulation of DNA damage repair genes, leading to accumulation of DNA damage and sensitization to talazoparib or chemotherapy in vitro. In patient-derived xenograft mouse models, splicing modulators reduced cohesin-mutant cancer burden, and sequential treatment with talazoparib or doxorubicin and cytarabine significantly improved survival. These findings suggest that splicing modulators may be useful for the treatment of cohesin-mutant cancers. —Melissa L. Norton [ABSTRACT FROM AUTHOR]

The FACT (FAcilitates Chromatin Transactions) complex is a conserved complex that maintains chromatin structure on transcriptionally active genes. Consistent with this, FACT is enriched on highly expressed genes, but how it is targeted to these regions is unknown. In vitro, FACT binds destabilized nucleosomes, supporting the hypothesis that FACT is targeted to transcribed chromatin through recognition of RNA polymerase (RNAP)-disrupted nucleosomes. In this study, we used high-resolution analysis of FACT occupancy in Saccharomyces cerevisiae to test this hypothesis. We demonstrate that FACT interacts with nucleosomes in vivo and that its interaction with chromatin is dependent on transcription by any of the three RNAPs. Deep sequencing of micrococcal nuclease-resistant fragments shows that FACT-bound nucleosomes exhibit differing nuclease sensitivity compared to bulk chromatin, consistent with a modified nucleosome structure being the preferred ligand for this complex. Interestingly, a subset of FACT-bound nucleosomes may be "overlapping dinucleosomes," in which one histone octamer invades the ~147-bp territory normally occupied by the adjacent nucleosome. While the differing nuclease sensitivity of FACT-bound nucleosomes could also be explained by the demonstrated ability of FACT to alter nucleosome structure, transcription inhibition restores nuclease resistance, suggesting that it is not due to FACT interaction alone. Collectively, these results are consistent with a model in which FACT is targeted to transcribed genes through preferential interaction with RNAP-disrupted nucleosomes. [ABSTRACT FROM AUTHOR]

The article discusses the potential role of CDK13, a transcriptional cyclin-dependent kinase, as a therapeutic target for melanoma. Topics include examines the researchers observed an enrichment of CDK13 kinase domain mutations in melanoma patients, suggesting that CDK13 functions as a dominant-negative tumor suppressor.