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A conceptual framework for the identification of candidate drugs and drug targets in acute promyelocytic leukemia

Marstrand, T. T.; Borup, R.; Willer, A.; Borregaard, N.; Sandelin, A.; Porse, B. T. and Theilgaard-Moench, Kim LU (2010) In Leukemia 24(7). p.1265-1275
Abstract
Chromosomal translocations of transcription factors generating fusion proteins with aberrant transcriptional activity are common in acute leukemia. In acute promyelocytic leukemia (APL), the promyelocytic leukemia-retinoic-acid receptor alpha (PML-RARA) fusion protein, which emerges as a consequence of the t(15;17) translocation, acts as a transcriptional repressor that blocks neutrophil differentiation at the promyelocyte (PM) stage. In this study, we used publicly available microarray data sets and identified signatures of genes dysregulated in APL by comparison of gene expression profiles of APL cells and normal PMs representing the same stage of differentiation. We next subjected our identified APL signatures of dysregulated genes to a... (More)
Chromosomal translocations of transcription factors generating fusion proteins with aberrant transcriptional activity are common in acute leukemia. In acute promyelocytic leukemia (APL), the promyelocytic leukemia-retinoic-acid receptor alpha (PML-RARA) fusion protein, which emerges as a consequence of the t(15;17) translocation, acts as a transcriptional repressor that blocks neutrophil differentiation at the promyelocyte (PM) stage. In this study, we used publicly available microarray data sets and identified signatures of genes dysregulated in APL by comparison of gene expression profiles of APL cells and normal PMs representing the same stage of differentiation. We next subjected our identified APL signatures of dysregulated genes to a series of computational analyses leading to (i) the finding that APL cells show stem cell properties with respect to gene expression and transcriptional regulation, and (ii) the identification of candidate drugs and drug targets for therapeutic interventions. Significantly, our study provides a conceptual framework that can be applied to any subtype of AML and cancer in general to uncover novel information from published microarray data sets at low cost. In a broader perspective, our study provides strong evidence that genomic strategies might be used in a clinical setting to prospectively identify candidate drugs that subsequently are validated in vitro to define the most effective drug combination for individual cancer patients on a rational basis. Leukemia (2010) 24, 1265-1275; doi:10.1038/leu.2010.95; published online 27 May 2010 (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
MAP(CMAP), gene set enrichment analysis (GSEA), connectivity, gene expression profiling, drug discovery, AML, stemness
in
Leukemia
volume
24
issue
7
pages
1265 - 1275
publisher
Nature Publishing Group
external identifiers
  • wos:000279892900004
  • scopus:77954658244
ISSN
1476-5551
DOI
10.1038/leu.2010.95
language
English
LU publication?
yes
id
602dc4f5-90b8-4425-bb52-b11730c97a28 (old id 1657388)
date added to LUP
2010-08-30 13:06:27
date last changed
2018-05-29 10:32:04
@article{602dc4f5-90b8-4425-bb52-b11730c97a28,
  abstract     = {Chromosomal translocations of transcription factors generating fusion proteins with aberrant transcriptional activity are common in acute leukemia. In acute promyelocytic leukemia (APL), the promyelocytic leukemia-retinoic-acid receptor alpha (PML-RARA) fusion protein, which emerges as a consequence of the t(15;17) translocation, acts as a transcriptional repressor that blocks neutrophil differentiation at the promyelocyte (PM) stage. In this study, we used publicly available microarray data sets and identified signatures of genes dysregulated in APL by comparison of gene expression profiles of APL cells and normal PMs representing the same stage of differentiation. We next subjected our identified APL signatures of dysregulated genes to a series of computational analyses leading to (i) the finding that APL cells show stem cell properties with respect to gene expression and transcriptional regulation, and (ii) the identification of candidate drugs and drug targets for therapeutic interventions. Significantly, our study provides a conceptual framework that can be applied to any subtype of AML and cancer in general to uncover novel information from published microarray data sets at low cost. In a broader perspective, our study provides strong evidence that genomic strategies might be used in a clinical setting to prospectively identify candidate drugs that subsequently are validated in vitro to define the most effective drug combination for individual cancer patients on a rational basis. Leukemia (2010) 24, 1265-1275; doi:10.1038/leu.2010.95; published online 27 May 2010},
  author       = {Marstrand, T. T. and Borup, R. and Willer, A. and Borregaard, N. and Sandelin, A. and Porse, B. T. and Theilgaard-Moench, Kim},
  issn         = {1476-5551},
  keyword      = {MAP(CMAP),gene set enrichment analysis (GSEA),connectivity,gene expression profiling,drug discovery,AML,stemness},
  language     = {eng},
  number       = {7},
  pages        = {1265--1275},
  publisher    = {Nature Publishing Group},
  series       = {Leukemia},
  title        = {A conceptual framework for the identification of candidate drugs and drug targets in acute promyelocytic leukemia},
  url          = {http://dx.doi.org/10.1038/leu.2010.95},
  volume       = {24},
  year         = {2010},
}