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

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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.; Theilgaard-Moench, Kim.

In: Leukemia, Vol. 24, No. 7, 2010, p. 1265-1275.

Research output: Contribution to journalArticle

Harvard

Marstrand, TT, Borup, R, Willer, A, Borregaard, N, Sandelin, A, Porse, BT & Theilgaard-Moench, K 2010, 'A conceptual framework for the identification of candidate drugs and drug targets in acute promyelocytic leukemia', Leukemia, vol. 24, no. 7, pp. 1265-1275. https://doi.org/10.1038/leu.2010.95

APA

Marstrand, T. T., Borup, R., Willer, A., Borregaard, N., Sandelin, A., Porse, B. T., & Theilgaard-Moench, K. (2010). A conceptual framework for the identification of candidate drugs and drug targets in acute promyelocytic leukemia. Leukemia, 24(7), 1265-1275. https://doi.org/10.1038/leu.2010.95

CBE

Marstrand TT, Borup R, Willer A, Borregaard N, Sandelin A, Porse BT, Theilgaard-Moench K. 2010. A conceptual framework for the identification of candidate drugs and drug targets in acute promyelocytic leukemia. Leukemia. 24(7):1265-1275. https://doi.org/10.1038/leu.2010.95

MLA

Vancouver

Author

Marstrand, T. T. ; Borup, R. ; Willer, A. ; Borregaard, N. ; Sandelin, A. ; Porse, B. T. ; Theilgaard-Moench, Kim. / A conceptual framework for the identification of candidate drugs and drug targets in acute promyelocytic leukemia. In: Leukemia. 2010 ; Vol. 24, No. 7. pp. 1265-1275.

RIS

TY - JOUR

T1 - A conceptual framework for the identification of candidate drugs and drug targets in acute promyelocytic leukemia

AU - Marstrand, T. T.

AU - Borup, R.

AU - Willer, A.

AU - Borregaard, N.

AU - Sandelin, A.

AU - Porse, B. T.

AU - Theilgaard-Moench, Kim

PY - 2010

Y1 - 2010

N2 - 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

AB - 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

KW - MAP(CMAP)

KW - gene set enrichment analysis (GSEA)

KW - connectivity

KW - gene expression profiling

KW - drug discovery

KW - AML

KW - stemness

U2 - 10.1038/leu.2010.95

DO - 10.1038/leu.2010.95

M3 - Article

VL - 24

SP - 1265

EP - 1275

JO - Leukemia : official journal of the Leukemia Society of America, Leukemia Research Fund, U.K

JF - Leukemia : official journal of the Leukemia Society of America, Leukemia Research Fund, U.K

SN - 1476-5551

IS - 7

ER -