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Learn MoreSplicing factor SF3B1 is frequently mutated in chronic lymphocytic leukemia (CLL) patients and has been suggested as a potential therapeutic target. In this study, we performed RNA-seq analysis to evaluate the global impact of SF3B1 modulator sudemycin D6 (SD6) on alternative splicing. Our analysis revealed significant increases in global intron-retention in SD6-treated CLL cells. Pathway analysis of the genes associated with increased intron-retention suggested that B-cell receptor (BCR), protein ubiquitination, and PI3K signaling pathways were among the top canonical pathways being affected by SD6. The increases in intron-retention were inversely correlated with deceases in mRNA and protein levels of the affected BCR/PI3K pathway molecules such as BLNK, BTK, AKT1, PLC2 and PI3K. SD6 also induced a time-dependent exon-skipping event in mRNA of MCL1 and resulted in significant down-regulation of another anti-apoptotic gene TRAF1, which may contribute to the SD6-induced apoptosis. Finally, SD6 can overcome the pro-survival and pro-growth signals and synergize with ibrutinib, idelalisib and venetoclax to induce apoptosis in primary CLL cells co-cultured with bone marrow stromal cells and in the presence of T-cell-derived cytokines. Cumulatively, these results provide a strong rationale for future clinical development of spliceosome modulators and combinatory therapies based on spliceosome modulators in CLL. SOURCE: Huidong Shi (hshi@augusta.edu) - 2125 K Augusta University
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