Proof of the concept to use a malignant B cell line drug screen strategy for identification and weight of melphalan resistance genes in multiple myeloma.

In a conceptual study of drug resistance we have used a preclinical model of malignant B-cell lines by combining drug induced growth inhibition and gene expression profiling. In the current report a melphalan resistance profile of 19 genes were weighted by microarray data from the MRC Myeloma IX tri...

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Autores principales:	Martin Bøgsted, Anders E Bilgrau, Christopher P Wardell, Uta Bertsch, Alexander Schmitz, Julie S Bødker, Malene K Kjeldsen, Hartmut Goldschmidt, Gareth J Morgan, Karen Dybkaer, Hans E Johnsen
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2013
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/0778cf153500471da18c26b6bab43813
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spelling	oai:doaj.org-article:0778cf153500471da18c26b6bab438132021-11-18T08:40:54ZProof of the concept to use a malignant B cell line drug screen strategy for identification and weight of melphalan resistance genes in multiple myeloma.1932-620310.1371/journal.pone.0083252https://doaj.org/article/0778cf153500471da18c26b6bab438132013-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/24376673/pdf/?tool=EBIhttps://doaj.org/toc/1932-6203In a conceptual study of drug resistance we have used a preclinical model of malignant B-cell lines by combining drug induced growth inhibition and gene expression profiling. In the current report a melphalan resistance profile of 19 genes were weighted by microarray data from the MRC Myeloma IX trial and time to progression following high dose melphalan, to generate an individual melphalan resistance index. The resistance index was subsequently validated in the HOVON65/GMMG-HD4 trial data set to prove the concept. Biologically, the assigned resistance indices were differentially distributed among translocations and cyclin D expression classes. Clinically, the 25% most melphalan resistant, the intermediate 50% and the 25% most sensitive patients had a median progression free survival of 18, 32 and 28 months, respectively (log-rank P-value = 0.05). Furthermore, the median overall survival was 45 months for the resistant group and not reached for the intermediate and sensitive groups (log-rank P-value = 0.003) following 38 months median observation. In a multivariate analysis, correcting for age, sex and ISS-staging, we found a high resistance index to be an independent variable associated with inferior progression free survival and overall survival. This study provides clinical proof of concept to use in vitro drug screen for identification of melphalan resistance gene signatures for future functional analysis.Martin BøgstedAnders E BilgrauChristopher P WardellUta BertschAlexander SchmitzJulie S BødkerMalene K KjeldsenHartmut GoldschmidtGareth J MorganKaren DybkaerHans E JohnsenPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 8, Iss 12, p e83252 (2013)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Martin Bøgsted Anders E Bilgrau Christopher P Wardell Uta Bertsch Alexander Schmitz Julie S Bødker Malene K Kjeldsen Hartmut Goldschmidt Gareth J Morgan Karen Dybkaer Hans E Johnsen Proof of the concept to use a malignant B cell line drug screen strategy for identification and weight of melphalan resistance genes in multiple myeloma.
description	In a conceptual study of drug resistance we have used a preclinical model of malignant B-cell lines by combining drug induced growth inhibition and gene expression profiling. In the current report a melphalan resistance profile of 19 genes were weighted by microarray data from the MRC Myeloma IX trial and time to progression following high dose melphalan, to generate an individual melphalan resistance index. The resistance index was subsequently validated in the HOVON65/GMMG-HD4 trial data set to prove the concept. Biologically, the assigned resistance indices were differentially distributed among translocations and cyclin D expression classes. Clinically, the 25% most melphalan resistant, the intermediate 50% and the 25% most sensitive patients had a median progression free survival of 18, 32 and 28 months, respectively (log-rank P-value = 0.05). Furthermore, the median overall survival was 45 months for the resistant group and not reached for the intermediate and sensitive groups (log-rank P-value = 0.003) following 38 months median observation. In a multivariate analysis, correcting for age, sex and ISS-staging, we found a high resistance index to be an independent variable associated with inferior progression free survival and overall survival. This study provides clinical proof of concept to use in vitro drug screen for identification of melphalan resistance gene signatures for future functional analysis.
format	article
author	Martin Bøgsted Anders E Bilgrau Christopher P Wardell Uta Bertsch Alexander Schmitz Julie S Bødker Malene K Kjeldsen Hartmut Goldschmidt Gareth J Morgan Karen Dybkaer Hans E Johnsen
author_facet	Martin Bøgsted Anders E Bilgrau Christopher P Wardell Uta Bertsch Alexander Schmitz Julie S Bødker Malene K Kjeldsen Hartmut Goldschmidt Gareth J Morgan Karen Dybkaer Hans E Johnsen
author_sort	Martin Bøgsted
title	Proof of the concept to use a malignant B cell line drug screen strategy for identification and weight of melphalan resistance genes in multiple myeloma.
title_short	Proof of the concept to use a malignant B cell line drug screen strategy for identification and weight of melphalan resistance genes in multiple myeloma.
title_full	Proof of the concept to use a malignant B cell line drug screen strategy for identification and weight of melphalan resistance genes in multiple myeloma.
title_fullStr	Proof of the concept to use a malignant B cell line drug screen strategy for identification and weight of melphalan resistance genes in multiple myeloma.
title_full_unstemmed	Proof of the concept to use a malignant B cell line drug screen strategy for identification and weight of melphalan resistance genes in multiple myeloma.
title_sort	proof of the concept to use a malignant b cell line drug screen strategy for identification and weight of melphalan resistance genes in multiple myeloma.
publisher	Public Library of Science (PLoS)
publishDate	2013
url	https://doaj.org/article/0778cf153500471da18c26b6bab43813
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Proof of the concept to use a malignant B cell line drug screen strategy for identification and weight of melphalan resistance genes in multiple myeloma.

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