Shooting the messenger (RNA) in B-cell lymphoma

In this issue of Blood, Culjkovic-Kraljacic et al demonstrate that targeted inhibition of the messenger RNA (mRNA) translation initiation factor eIF4E is an effective strategy to reduce expression of the MYC, B-cell lymphoma (BCL)2, and BCL6 oncoproteins in aggressive BCLs.¹ 

mRNAs are the essential intermediates that convey genetic information from genes to their protein products. Transcription, the process by which DNA is first converted into mRNA, has been studied in depth; mRNA expression profiling has provided remarkable insight into the pathogenesis of hematologic malignancies and small molecule inhibition of epigenetic regulators of transcription remains an important area for drug development. However, it is also clear that mRNAs are not just passive conveyers of genetic information but are themselves subject to tight regulation. mRNAs form dynamic 3-dimensional structures with multiple RNA:RNA and RNA:protein interactions that influence function.²  mRNAs are also the target for modulatory effects of microRNAs, frequently dysregulated in cancer. Thus, the export of mRNAs from the nucleus to the cytoplasm, mRNA translation, and mRNA degradation are all tightly controlled processes.

In light of the tight regulation normally imposed on mRNA, it is not surprising that alterations in these processes play significant roles in many cancers, including hematologic malignancies. For example, the eukaryotic initiation factor eIF4E is a core component of the translational preinitiation complex and recognizes the m⁷G 5′-cap structure of mRNAs. mRNAs encoding oncoproteins are often highly dependent on eIF4E for efficient translation and are therefore particularly sensitive to decreased eIF4E expression/function.³  eIF4E is frequently overexpressed in B-cell malignancies, especially in more aggressive subtypes,⁴  and eIF4E cooperates with MYC to drive B-cell lymphomagenesis in mouse models.⁵  Other eukaryotic initiation factors also appear to contribute to dysregulated mRNA translation in lymphoma. For example, eIF4B overexpression in diffuse large BCL (DLBCL) has been linked to altered cell survival and DNA damage response pathways.⁶  In light of such findings, targeted inhibition of mRNA translation has become an active area for drug development. The translational elongation inhibitor omacetaxine mepesuccinate (homoharringtonine) is approved for the treatment of chronic myeloid leukemia, and other compounds are in preclinical and clinical development for a wide range of cancer types.⁷ 

The study by Culjkovic-Kraljacic et al provides important new insight into the role of eIF4E in aggressive BCLs.¹  Their study focused on double- and triple-hit (DH/TH) DLBCL. These tumors are characterized by activating mutations leading to enhanced expression of MYC, and BCL2 and/or BCL6, and are particularly difficult to treat. The authors show that eIF4E was often highly expressed in DLBCL tumor biopsies and that RNA interference–mediated eIF4E knockdown in lymphoma-derived cell lines resulted in decreased expression of MYC, BCL2, and BCL6 (see figure). eIF4E RNA-immunoprecipitation was used to “capture” eIF4E-associated mRNAs and demonstrated directly that eIF4E bound BCL6, BCL2, and MYC mRNAs. eIF4E also interacted with many other mRNAs encoding proteins involved in B-cell receptor signaling, metabolism, and DNA repair, suggesting a broad role for eIF4E in maintaining pro-lymphoma protein expression. Stimulatory effects of eIF4E on expression of its target mRNAs appeared to involve increased mRNA export from the nucleus,⁸  perhaps acting in addition to enhanced target mRNA translation. Importantly, the antiviral drug ribavirin, which can act as an m⁷G 5′-cap mimic and interfere with binding between eIF4E and its mRNA substrates, also reduced MYC, BCL2, and BCL6 expression in B-cell lines in vitro. Ribavirin also effectively suppressed growth of a xenografted primary DLBCL sample in immunocompromised mice.

Another notable finding revealed by the study was the functional interplay between eIF4E and heat shock proteins. Tumor cells frequently contain relatively high levels of a “stress active” form of Hsp90 termed TEHsp90, which is required to maintain malignant cell viability and proliferation. Hsp90 inhibitors, including PU-H71, have shown promising preclinical activity in B-cell malignancies;⁹  however, cellular responses are typically limited by feedback induction of another chaperone, Hsp70B. Culjkovic-Kraljacic et al showed that eIF4E was a TEHsp90 client protein in BCL cell lines and that, in turn, eIF4E was required for PU–H71-induced Hsp70B expression.¹  Moreover, the combination of ribavirin and PU-H71 exerted stronger antilymphoma activity in vivo compared with either drug alone. There may be many mechanisms of crosstalk between PU-H71 and ribavirin, but the study suggests that ribavirin interferes with eIF4E-mediated feedback induction of Hsp70B following TEHsp90 inhibition (see figure).

Overall, this study provides important new insight into the role of eIF4E and mRNA control in B-cell cancers. eIF4E’s contribution may be multifunctional, and further studies are required to dissect the relative contribution of effects on nuclear export and mRNA translation. Although the study focused on DH/TH lymphoma, the applicability of these results to other tumors lacking genetic dysregulation of MYC, BCL2, and/or BCL6 also requires further study. It will also be important to investigate whether these functions of eIF4E are modulated by posttranslational modification, eg, via mitogen-activated protein kinase interacting kinase (MNK)-kinase dependent phosphorylation.¹⁰  Moreover, ribavirin may exert its anti-lymphoma effects act via effects on targets, in addition to eIF4E. Regardless, the growing attention that is being focused on mRNA is revealing fascinating insight into lymphoma biology. This promises to be a fruitful area for the discovery of new anticancer drugs.