Targeted inhibition of eIF4A suppresses B-cell receptor-induced translation and expression of MYC and MCL1 in chronic lymphocytic leukemia cells
| Autor: | Andrew J. Steele, Freda K. Stevenson, Joe Taylor, Mark J. Coldwell, Graham Packham, Sarah Wilmore, Elizabeth Lemm, Alison Yeomans, Francesco Forconi, Rachel Fell, Karly-Rai Rogers-Broadway |
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| Rok vydání: | 2021 |
| Předmět: |
mRNA translation
RNA Stability Chronic lymphocytic leukemia B-cell receptor Receptors Antigen B-Cell MYC Silvestrol Proto-Oncogene Proteins c-myc Cellular and Molecular Neuroscience hemic and lymphatic diseases medicine Humans Initiation factor MCL1 RNA Messenger Molecular Biology Cells Cultured Benzofurans Pharmacology Chemistry breakpoint cluster region Translation (biology) Cell Biology MRNA stabilization medicine.disease Leukemia Lymphocytic Chronic B-Cell Triterpenes Antibodies Anti-Idiotypic Protein Biosynthesis eIF4A Eukaryotic Initiation Factor-4A Leukocytes Mononuclear Cancer research Myeloid Cell Leukemia Sequence 1 Protein Molecular Medicine Original Article Rocaglamide Signal Transduction |
| Zdroj: | Cellular and Molecular Life Sciences |
| ISSN: | 1420-9071 1420-682X |
| DOI: | 10.1007/s00018-021-03910-x |
| Popis: | Signaling via the B-cell receptor (BCR) is a key driver and therapeutic target in chronic lymphocytic leukemia (CLL). BCR stimulation of CLL cells induces expression of eIF4A, an initiation factor important for translation of multiple oncoproteins, and reduces expression of PDCD4, a natural inhibitor of eIF4A, suggesting that eIF4A may be a critical nexus controlling protein expression downstream of the BCR in these cells. We, therefore, investigated the effect of eIF4A inhibitors (eIF4Ai) on BCR-induced responses. We demonstrated that eIF4Ai (silvestrol and rocaglamide A) reduced anti-IgM-induced global mRNA translation in CLL cells and also inhibited accumulation of MYC and MCL1, key drivers of proliferation and survival, respectively, without effects on upstream signaling responses (ERK1/2 and AKT phosphorylation). Analysis of normal naïve and non-switched memory B cells, likely counterparts of the two main subsets of CLL, demonstrated that basal RNA translation was higher in memory B cells, but was similarly increased and susceptible to eIF4Ai-mediated inhibition in both. We probed the fate of MYC mRNA in eIF4Ai-treated CLL cells and found that eIF4Ai caused a profound accumulation of MYC mRNA in anti-IgM treated cells. This was mediated by MYC mRNA stabilization and was not observed for MCL1 mRNA. Following drug wash-out, MYC mRNA levels declined but without substantial MYC protein accumulation, indicating that stabilized MYC mRNA remained blocked from translation. In conclusion, BCR-induced regulation of eIF4A may be a critical signal-dependent nexus for therapeutic attack in CLL and other B-cell malignancies, especially those dependent on MYC and/or MCL1. |
| Databáze: | OpenAIRE |
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