Translation Inhibition through eIF4A1 Targeting in Multiple Myeloma Is a Promising Therapeutic Strategy

Multiple Myeloma (MM) is a plasma cell (PC) disorder without definitive treatment and associated with multiple relapses. There is therefore an urgent need to develop innovative therapeutic strategies to overcome drug resistance. mRNA translation deregulation in involved in cancer progression by prom...

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Published in:Blood 2023-11, Vol.142 (Supplement 1), p.1924-1924
Main Authors: Dutrieux, Laure, Loughran, Elle, Choquet, Armelle, Herault, Hélène, Guillemin, Antoine, Robert, Nicolas, Requirand, Guilhem, Cartron, Guillaume, Vincent, Laure, Herbaux, Charles, Rivals, Eric, David, Alexandre, Moreaux, Jerome
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Language:English
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Summary:Multiple Myeloma (MM) is a plasma cell (PC) disorder without definitive treatment and associated with multiple relapses. There is therefore an urgent need to develop innovative therapeutic strategies to overcome drug resistance. mRNA translation deregulation in involved in cancer progression by promoting aberrant proliferation or cell survival, and several translation factors such as eIF4A1 are deregulated in cancer, pointing to an addiction to high protein synthesis. In this context, inhibitors of eIF4A1-mediated translation have been developed and have shown anti-tumor effects in several models of hematological malignancies. Targeting translation in MM with eIF4A1 inhibition thus represent a potential treatment strategy in MM. To evaluate the therapeutic interest of targeting eIF4A1 in MM, we analyzed its expression in Bone Marrow Plasma Cells (BMPC, n = 22), Monoclonal Gammopathy of Unknown Significance cells (MGUS, n = 44), Smoldering MM Cells (SMMC, n = 12), MM cells (MMC, n = 345), and Human Myeloma Cell Lines (HMCLs, n = 42). We found that eIF4A1 expression increased throughout the evolution of the disease with a highest expression in HMCLs, and was significantly upregulated in the molecular subgroups Proliferation and Hyperdiploid (UAMS, TT2 cohort). Importantly, eIF4A1 high expression was associated with a poor prognosis in two independent cohorts of MM, a cohort of newly diagnosed patients treated by high dose therapy and autologous stem cell transplantation (UAMS, TT2 cohort, n = 345) and a cohort of patients at relapse treated with Proteasome Inhibitors (Mulligan, n = 188). Gene Set Enrichment Analysis (GSEA) of genes expressed in eIF4A1 high patients compared to eIF4A1 low patients revealed an enrichment in pathways related to RNA metabolism, DNA repair, epigenetic regulation and plasmablastic signature. We investigated the impact of eIF4A1 inhibition using Rocaglamide (Roca) in HMCLs. Roca was highly cytotoxic for 13 HMCLs with an IC50 < 20nM, led to cell cycle deregulation and to the downregulation of MMSET, MYC, IKAROS and EZH2 expression. Importantly, using a co-culture of primary MM cells with normal cells from the bone marrow micro-environment, we found that Roca was cytotoxic for malignant PCs but not bone marrow cells (n = 5). To deeper characterize eIF4A1 targets in MM cells, we performed Polysome Profiling to measure translational efficiency depending on the level of ribosomes associated with individual mRNAs. Roca induced a strong i
ISSN:0006-4971
1528-0020
DOI:10.1182/blood-2023-184749