Inhibition of mRNA translation initiation factors as novel therapeutic approach in chronic lymphocytic leukaemia (CLL)

Abstract

Signalling via the B-cell receptor (BCR) is a major driver of disease progression in chronic lymphocytic leukaemia (CLL) and an established target for therapeutic attack. Studies have demonstrated that BCR-stimulation of CLL cells leads to a substantial increase in global mRNA translation and enhanced translation of oncoprotein MYC. Increased translation is associated with increased expression of eukaryotic initiation factor-4A (eIF4A) in CLL cells, but not in healthy donor B cells, and high expression of eIF4E has been documented in CLL compared to normal B cells. This suggested that it may be possible to selectively inhibit global and/or MYC mRNA translation in CLL cells using inhibitors targeted against specific components of the translation machinery. I therefore investigated the effects of inhibitors of eIF4A, silvestrol and rocaglamide, and an eIF4E inhibitor, ribavirin in CLL.Both eIF4A inhibitors (eIF4Ai) and ribavirin reduced anti-IgM-induced global mRNA translation in primary CLL cells, analysed using O-propargy 1-puromycin (OPP)-labelling. Inhibition of eIF4A resulted in reduced translation of MYC, as well as MCL1, a BCL-2 family protein which, like MYC, is linked to poor outcome. Whilst MYC protein expression was reduced, this was associated with a surprising increase in MYC mRNA expression, via increased RNA stabilisation. Although, eIF4Ai inhibited mRNA translation in healthy donor B cells, inhibition of eIF4E had no effect on translation in B cells from healthy donors. eIF4E also has a role in the nuclear export of specific eIF4E-target mRNAs, including MYC. Ribavirin reduced the nuclear export of mRNA encoding proliferation promoting CCND1 and MYC in CLL samples. In vivo studies utilising ribavirin treatment in mice bearing Eμ-TCL1 leukaemic cells, showed efficacy by reduced tumour burden. Overall, these results support the hypothesis that inhibition of the translation initiation machinery is an effective strategy to suppress anti-IgM-induced translation in CLL cells, to deprive malignant cells of the tumour-promoting effects of oncoproteins such as MYC and MCL1