Lenalidomide modulates gene expression in human ABC-DLBCL cells by regulating IKAROS interaction with an intronic control region of SPIB.

Activated B-cell diffuse large B-cell lymphoma (ABC-DLBCL) is associated with a poor prognosis compared with other DLBCL types and therefore represents a top priority for developing novel therapies. Lenalidomide, an immunomodulatory drug in trials for treatment of ABC-DLBCL, targets the transcription factor for degradation by the cereblon E3 ubiquitin ligase complex. In this study, we investigated whether the gene encoding the transcription factor SPI-B is a target of Using cultured ABC-DLBCL cell lines, we found that high levels of SPI-B expression conferred resistance to lenalidomide. Lenalidomide treatment of ABC-DLBCL cells resulted in downregulation of SPIB at the level of transcription. SPIB was regulated directly by IKAduanyu1670 through a binding site located in the first intron of the gene. Inhibition of IKAduanyu1670 binding using CRISPR/Cas9-mediated transcriptional repression downregulated endogenous SPIB transcription. Finally, ectopic expression of IKAduanyu1670 protected SPIB from downregulation. These results show that the mechanism of action of lenalidomide in ABC-DLBCL cells involves downregulation of SPIB transcription by cereblon-induced degradation of IKAduanyu1670. These results have implications for the design of synthetic lethal therapy for the treatment of ABC-DLBCL.

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