About: The mevalonate pathway is an actionable vulnerability of t(4;14)-positive multiple myeloma

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About: The mevalonate pathway is an actionable vulnerability of t(4;14)-positive multiple myeloma Goto Sponge NotDistinct Permalink

An Entity of Type : schema:ScholarlyArticle, within Data Space : wasabi.inria.fr associated with source document(s)

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type	Academic Article research paper schema:ScholarlyArticle
isDefinedBy	Covid-on-the-Web dataset
title	The mevalonate pathway is an actionable vulnerability of t(4;14)-positive multiple myeloma
Creator	David, • Licht, Jonathan Branchard, Emily Haibe-Kains, Benjamin Keats, Jonathan Li, Zhihua Longo, Joseph Penn, Linda Pugh, Trevor Smirnov, Petr Trudel, Suzanne Andrews, W Van Leeuwen, Jenna
source	Medline; PMC
abstract	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.
has issue date	2020-07-14(xsd:dateTime)
bibo:doi	10.1038/s41375-020-0962-2
bibo:pmid	32665698
has license	cc-by
sha1sum (hex)	81f8cfbddbf83644966f19a7d5a2a871fb000d1a
schema:url	https://doi.org/10.1038/s41375-020-0962-2
resource representing a document's title	The mevalonate pathway is an actionable vulnerability of t(4;14)-positive multiple myeloma
has PubMed Central identifier	PMC7359767
has PubMed identifier	32665698
schema:publication	Leukemia
resource representing a document's body	covid:81f8cfbddbf83644966f19a7d5a2a871fb000d1a#body_text
is schema:about of	named entity 'biomarker' named entity 'malignancy' named entity 'positive' named entity 'mevalonate' named entity 'induced' named entity 'Our' named entity 'bortezomib' named entity 'positive' named entity 'fluvastatin' named entity 'subtype' named entity 'evaluation' named entity 'plasma cell' named entity 'apoptosis' named entity 'metabolic' named entity 'warrant' named entity 'translocation' named entity 'proteasome inhibitor' named entity 'statin' named entity 'bortezomib' named entity 'geranylgeranylation' named entity 'Multiple myeloma' named entity 'biomarker' named entity 'ISR' named entity 'GGPP' named entity 'apoptosis' named entity 'apoptosis' named entity 'mevalonate pathway' named entity 'multiple myeloma' named entity 'solvent' named entity 'statin' named entity 'preclinical' named entity 'dead cells' named entity 'treat patients' named entity 'Statin' named entity 'cell lines' named entity 'statin' named entity 'cell lines' named entity 'GGPP' named entity 'fluvastatin' named entity 'tumors' named entity 'biological processes' named entity 'lovastatin' named entity 'bortezomib' named entity 'mammalian cells' named entity 'cell death' named entity 'statin' named entity 'dead cells' named entity 'multiple comparisons' named entity 'solvent' named entity 'lovastatin' named entity 'cell lines' named entity 'cell lines' named entity '14q32' named entity 'cell lines' named entity 'dipyridamole' named entity 'cell death' named entity 'subcutaneously' named entity 'Lonza' named entity 'rate-limiting enzyme' named entity 'intraperitoneally' named entity 'fluvastatin' named entity 'Annexin' named entity 'flow cytometry' named entity 'mice' named entity 'ATF3' named entity 'transcription factors' named entity 'ATF4' named entity 'fluvastatin' named entity 'statin'

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