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Targeted inhibition of eIF4A suppresses B-cell receptor-induced translation and expression of MYC and MCL1 in chronic lymphocytic leukemia cells

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 inhibito...

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Autores principales: Wilmore, Sarah, Rogers-Broadway, Karly-Rai, Taylor, Joe, Lemm, Elizabeth, Fell, Rachel, Stevenson, Freda K., Forconi, Francesco, Steele, Andrew J., Coldwell, Mark, Packham, Graham, Yeomans, Alison
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Springer International Publishing 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8429177/
https://www.ncbi.nlm.nih.gov/pubmed/34398253
http://dx.doi.org/10.1007/s00018-021-03910-x
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author Wilmore, Sarah
Rogers-Broadway, Karly-Rai
Taylor, Joe
Lemm, Elizabeth
Fell, Rachel
Stevenson, Freda K.
Forconi, Francesco
Steele, Andrew J.
Coldwell, Mark
Packham, Graham
Yeomans, Alison
author_facet Wilmore, Sarah
Rogers-Broadway, Karly-Rai
Taylor, Joe
Lemm, Elizabeth
Fell, Rachel
Stevenson, Freda K.
Forconi, Francesco
Steele, Andrew J.
Coldwell, Mark
Packham, Graham
Yeomans, Alison
author_sort Wilmore, Sarah
collection PubMed
description 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. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s00018-021-03910-x.
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spelling pubmed-84291772021-09-29 Targeted inhibition of eIF4A suppresses B-cell receptor-induced translation and expression of MYC and MCL1 in chronic lymphocytic leukemia cells Wilmore, Sarah Rogers-Broadway, Karly-Rai Taylor, Joe Lemm, Elizabeth Fell, Rachel Stevenson, Freda K. Forconi, Francesco Steele, Andrew J. Coldwell, Mark Packham, Graham Yeomans, Alison Cell Mol Life Sci Original Article 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. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s00018-021-03910-x. Springer International Publishing 2021-08-16 2021 /pmc/articles/PMC8429177/ /pubmed/34398253 http://dx.doi.org/10.1007/s00018-021-03910-x Text en © The Author(s) 2021 https://creativecommons.org/licenses/by/4.0/Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Original Article
Wilmore, Sarah
Rogers-Broadway, Karly-Rai
Taylor, Joe
Lemm, Elizabeth
Fell, Rachel
Stevenson, Freda K.
Forconi, Francesco
Steele, Andrew J.
Coldwell, Mark
Packham, Graham
Yeomans, Alison
Targeted inhibition of eIF4A suppresses B-cell receptor-induced translation and expression of MYC and MCL1 in chronic lymphocytic leukemia cells
title Targeted inhibition of eIF4A suppresses B-cell receptor-induced translation and expression of MYC and MCL1 in chronic lymphocytic leukemia cells
title_full Targeted inhibition of eIF4A suppresses B-cell receptor-induced translation and expression of MYC and MCL1 in chronic lymphocytic leukemia cells
title_fullStr Targeted inhibition of eIF4A suppresses B-cell receptor-induced translation and expression of MYC and MCL1 in chronic lymphocytic leukemia cells
title_full_unstemmed Targeted inhibition of eIF4A suppresses B-cell receptor-induced translation and expression of MYC and MCL1 in chronic lymphocytic leukemia cells
title_short Targeted inhibition of eIF4A suppresses B-cell receptor-induced translation and expression of MYC and MCL1 in chronic lymphocytic leukemia cells
title_sort targeted inhibition of eif4a suppresses b-cell receptor-induced translation and expression of myc and mcl1 in chronic lymphocytic leukemia cells
topic Original Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8429177/
https://www.ncbi.nlm.nih.gov/pubmed/34398253
http://dx.doi.org/10.1007/s00018-021-03910-x
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