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

被引：0
作者：
T T Marstrand
R Borup
A Willer
N Borregaard
A Sandelin
B T Porse
K Theilgaard-Mönch
机构：
[1] Biotech Research and Innovation Center,Department of Biology
[2] University of Copenhagen,Department of Clinical Biochemistry
[3] The Bioinformatics Centre,Department of Clinical Biochemistry
[4] University of Copenhagen,Department of Hematology
[5] Rigshospitalet,Department of Hematology
[6] University of Copenhagen,undefined
[7] Copenhagen,undefined
[8] The Laboratory for Gene Therapy Research,undefined
[9] Rigshospitalet,undefined
[10] University of Copenhagen,undefined
[11] The Granulocyte Research Laboratory,undefined
[12] Rigshospitalet,undefined
[13] University of Copenhagen,undefined
[14] Lund University Hospital,undefined
[15] Lund University,undefined
来源：
Leukemia | 2010年 / 24卷
关键词：
AML; stemness; drug discovery; gene expression profiling; connectivity MAP(CMAP); gene set enrichment analysis (GSEA);
D O I：
暂无
中图分类号：
学科分类号：
摘要：
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.
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页码：1265 / 1275
页数：10
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