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The mevalonate pathway is an actionable vulnerability of t(4;14)-positive multiple myeloma
Multiple myeloma (MM) is a plasma cell malignancy that is often driven by chromosomal translocations. In particular, patients with t(4;14)-positive disease have worse prognosis compared to other MM subtypes. Herein, we demonstrated that t(4;14)-positive cells are highly dependent on the mevalonate (...
Autores principales: | , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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Nature Publishing Group UK
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7359767/ https://www.ncbi.nlm.nih.gov/pubmed/32665698 http://dx.doi.org/10.1038/s41375-020-0962-2 |
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author | Longo, Joseph Smirnov, Petr Li, Zhihua Branchard, Emily van Leeuwen, Jenna E. Licht, Jonathan D. Haibe-Kains, Benjamin Andrews, David W. Keats, Jonathan J. Pugh, Trevor J. Trudel, Suzanne Penn, Linda Z. |
author_facet | Longo, Joseph Smirnov, Petr Li, Zhihua Branchard, Emily van Leeuwen, Jenna E. Licht, Jonathan D. Haibe-Kains, Benjamin Andrews, David W. Keats, Jonathan J. Pugh, Trevor J. Trudel, Suzanne Penn, Linda Z. |
author_sort | Longo, Joseph |
collection | PubMed |
description | Multiple myeloma (MM) is a plasma cell malignancy that is often driven by chromosomal translocations. In particular, patients with t(4;14)-positive disease have worse prognosis compared to other MM subtypes. Herein, we demonstrated that t(4;14)-positive cells are highly dependent on the mevalonate (MVA) pathway for survival. Moreover, we showed that this metabolic vulnerability is immediately actionable, as inhibiting the MVA pathway with a statin preferentially induced apoptosis in t(4;14)-positive cells. In response to statin treatment, t(4;14)-positive cells activated the integrated stress response (ISR), which was augmented by co-treatment with bortezomib, a proteasome inhibitor. We identified that t(4;14)-positive cells depend on the MVA pathway for the synthesis of geranylgeranyl pyrophosphate (GGPP), as exogenous GGPP fully rescued statin-induced ISR activation and apoptosis. Inhibiting protein geranylgeranylation similarly induced the ISR in t(4;14)-positive cells, suggesting that this subtype of MM depends on GGPP, at least in part, for protein geranylgeranylation. Notably, fluvastatin treatment synergized with bortezomib to induce apoptosis in t(4;14)-positive cells and potentiated the anti-tumor activity of bortezomib in vivo. Our data implicate the t(4;14) translocation as a biomarker of statin sensitivity and warrant further clinical evaluation of a statin in combination with bortezomib for the treatment of t(4;14)-positive disease. |
format | Online Article Text |
id | pubmed-7359767 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-73597672020-07-15 The mevalonate pathway is an actionable vulnerability of t(4;14)-positive multiple myeloma Longo, Joseph Smirnov, Petr Li, Zhihua Branchard, Emily van Leeuwen, Jenna E. Licht, Jonathan D. Haibe-Kains, Benjamin Andrews, David W. Keats, Jonathan J. Pugh, Trevor J. Trudel, Suzanne Penn, Linda Z. Leukemia Article Multiple myeloma (MM) is a plasma cell malignancy that is often driven by chromosomal translocations. In particular, patients with t(4;14)-positive disease have worse prognosis compared to other MM subtypes. Herein, we demonstrated that t(4;14)-positive cells are highly dependent on the mevalonate (MVA) pathway for survival. Moreover, we showed that this metabolic vulnerability is immediately actionable, as inhibiting the MVA pathway with a statin preferentially induced apoptosis in t(4;14)-positive cells. In response to statin treatment, t(4;14)-positive cells activated the integrated stress response (ISR), which was augmented by co-treatment with bortezomib, a proteasome inhibitor. We identified that t(4;14)-positive cells depend on the MVA pathway for the synthesis of geranylgeranyl pyrophosphate (GGPP), as exogenous GGPP fully rescued statin-induced ISR activation and apoptosis. Inhibiting protein geranylgeranylation similarly induced the ISR in t(4;14)-positive cells, suggesting that this subtype of MM depends on GGPP, at least in part, for protein geranylgeranylation. Notably, fluvastatin treatment synergized with bortezomib to induce apoptosis in t(4;14)-positive cells and potentiated the anti-tumor activity of bortezomib in vivo. Our data implicate the t(4;14) translocation as a biomarker of statin sensitivity and warrant further clinical evaluation of a statin in combination with bortezomib for the treatment of t(4;14)-positive disease. Nature Publishing Group UK 2020-07-14 2021 /pmc/articles/PMC7359767/ /pubmed/32665698 http://dx.doi.org/10.1038/s41375-020-0962-2 Text en © The Author(s) 2020 Open Access This 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 license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license 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 license, visit http://creativecommons.org/licenses/by/4.0/. |
spellingShingle | Article Longo, Joseph Smirnov, Petr Li, Zhihua Branchard, Emily van Leeuwen, Jenna E. Licht, Jonathan D. Haibe-Kains, Benjamin Andrews, David W. Keats, Jonathan J. Pugh, Trevor J. Trudel, Suzanne Penn, Linda Z. The mevalonate pathway is an actionable vulnerability of t(4;14)-positive multiple myeloma |
title | The mevalonate pathway is an actionable vulnerability of t(4;14)-positive multiple myeloma |
title_full | The mevalonate pathway is an actionable vulnerability of t(4;14)-positive multiple myeloma |
title_fullStr | The mevalonate pathway is an actionable vulnerability of t(4;14)-positive multiple myeloma |
title_full_unstemmed | The mevalonate pathway is an actionable vulnerability of t(4;14)-positive multiple myeloma |
title_short | The mevalonate pathway is an actionable vulnerability of t(4;14)-positive multiple myeloma |
title_sort | mevalonate pathway is an actionable vulnerability of t(4;14)-positive multiple myeloma |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7359767/ https://www.ncbi.nlm.nih.gov/pubmed/32665698 http://dx.doi.org/10.1038/s41375-020-0962-2 |
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