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Identification of p38β as a therapeutic target for the treatment of Sézary syndrome.

Bliss-Moreau M, Coarfa C, Gunaratne PH, Guitart J, Krett NL, Rosen ST - J. Invest. Dermatol. (2014)

Bottom Line: Gene set enrichment analysis uncovered candidate genes enriched for an immune-cell signature, specifically the T-cell receptor and mitogen-activated protein kinase signaling pathways.Further analysis identified p38 as a potential therapeutic target that is overexpressed in SS patients and decreased by synergistic-inhibitor treatment.This target was verified through small-molecule inhibition of p38, leading to cell death in both SS cell lines and patient cells.

View Article: PubMed Central - PubMed

Affiliation: Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA.

ABSTRACT
Cutaneous T-cell lymphomas (CTCLs) represent a group of hematopoietic malignancies that home to the skin and have no known molecular basis for disease pathogenesis. Sézary syndrome (SS) is the leukemic variant of CTCL. Currently, CTCL is incurable, highlighting the need for new therapeutic modalities. We have previously observed that combined small-molecule inhibition of protein kinase C-β (PKCβ) and glycogen synthase kinase 3 (GSK3) causes synergistic apoptosis in CTCL cell lines and patient cells. Through microarray analysis of a SS cell line, we surveyed global gene expression following combined PKCβ-GSK3 treatment to elucidate therapeutic targets responsible for cell death. Clinically relevant targets were defined as genes differentially expressed in SS patients that were modulated by combination-drug treatment of SS cells. Gene set enrichment analysis uncovered candidate genes enriched for an immune-cell signature, specifically the T-cell receptor and mitogen-activated protein kinase signaling pathways. Further analysis identified p38 as a potential therapeutic target that is overexpressed in SS patients and decreased by synergistic-inhibitor treatment. This target was verified through small-molecule inhibition of p38, leading to cell death in both SS cell lines and patient cells. These data establish p38 as a SS biomarker and a potential therapeutic target for the treatment of CTCL.

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Related in: MedlinePlus

Combined small-molecule microarray analysis and resultsGlobal gene expression analysis was performed on Hut78 cells treated for 3 days with Enz, ARA, and Enz+ARA. DMSO (vehicle) or no treatment cells served as controls. Four serial replicates were collected. (a) Venn diagrams of up- and down-regulated genes. (b) Hierarchical clustering of the 2,610 differentially regulated genes using Pearson’s Correlation Coefficient. (c) Combined Enz+ARA treatment enriches for an immune cell signature. GSEA was performed on combination-treatment gene signature (1807 total). TCR signaling, downstream p38α/β signaling, and nuclear β-catenin signaling pathways were enriched post Enz+ARA treatment.
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Figure 1: Combined small-molecule microarray analysis and resultsGlobal gene expression analysis was performed on Hut78 cells treated for 3 days with Enz, ARA, and Enz+ARA. DMSO (vehicle) or no treatment cells served as controls. Four serial replicates were collected. (a) Venn diagrams of up- and down-regulated genes. (b) Hierarchical clustering of the 2,610 differentially regulated genes using Pearson’s Correlation Coefficient. (c) Combined Enz+ARA treatment enriches for an immune cell signature. GSEA was performed on combination-treatment gene signature (1807 total). TCR signaling, downstream p38α/β signaling, and nuclear β-catenin signaling pathways were enriched post Enz+ARA treatment.

Mentions: To identify genes modulated by Enz+ARA that drive synergistic killing of Hut78 cells, we compared gene expression of all treatments against the vehicle treatment and performed comparisons between the transcriptome responses of each treatment group. 2,610 genes were significantly differentially expressed across all treatments, with 519 up-regulated and 1,288 down-regulated by Enz+ARA (Fold-Change (FC) >2, P<0.05). The Venn-diagram shows a greater overlap between ARA and combination-drug treatment than between Enz and combination-drug treatment (Figure 1a). This observation was reinforced by hierarchical clustering using Pearson’s Correlation Coefficient (Figure 1b).


Identification of p38β as a therapeutic target for the treatment of Sézary syndrome.

Bliss-Moreau M, Coarfa C, Gunaratne PH, Guitart J, Krett NL, Rosen ST - J. Invest. Dermatol. (2014)

Combined small-molecule microarray analysis and resultsGlobal gene expression analysis was performed on Hut78 cells treated for 3 days with Enz, ARA, and Enz+ARA. DMSO (vehicle) or no treatment cells served as controls. Four serial replicates were collected. (a) Venn diagrams of up- and down-regulated genes. (b) Hierarchical clustering of the 2,610 differentially regulated genes using Pearson’s Correlation Coefficient. (c) Combined Enz+ARA treatment enriches for an immune cell signature. GSEA was performed on combination-treatment gene signature (1807 total). TCR signaling, downstream p38α/β signaling, and nuclear β-catenin signaling pathways were enriched post Enz+ARA treatment.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4289446&req=5

Figure 1: Combined small-molecule microarray analysis and resultsGlobal gene expression analysis was performed on Hut78 cells treated for 3 days with Enz, ARA, and Enz+ARA. DMSO (vehicle) or no treatment cells served as controls. Four serial replicates were collected. (a) Venn diagrams of up- and down-regulated genes. (b) Hierarchical clustering of the 2,610 differentially regulated genes using Pearson’s Correlation Coefficient. (c) Combined Enz+ARA treatment enriches for an immune cell signature. GSEA was performed on combination-treatment gene signature (1807 total). TCR signaling, downstream p38α/β signaling, and nuclear β-catenin signaling pathways were enriched post Enz+ARA treatment.
Mentions: To identify genes modulated by Enz+ARA that drive synergistic killing of Hut78 cells, we compared gene expression of all treatments against the vehicle treatment and performed comparisons between the transcriptome responses of each treatment group. 2,610 genes were significantly differentially expressed across all treatments, with 519 up-regulated and 1,288 down-regulated by Enz+ARA (Fold-Change (FC) >2, P<0.05). The Venn-diagram shows a greater overlap between ARA and combination-drug treatment than between Enz and combination-drug treatment (Figure 1a). This observation was reinforced by hierarchical clustering using Pearson’s Correlation Coefficient (Figure 1b).

Bottom Line: Gene set enrichment analysis uncovered candidate genes enriched for an immune-cell signature, specifically the T-cell receptor and mitogen-activated protein kinase signaling pathways.Further analysis identified p38 as a potential therapeutic target that is overexpressed in SS patients and decreased by synergistic-inhibitor treatment.This target was verified through small-molecule inhibition of p38, leading to cell death in both SS cell lines and patient cells.

View Article: PubMed Central - PubMed

Affiliation: Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA.

ABSTRACT
Cutaneous T-cell lymphomas (CTCLs) represent a group of hematopoietic malignancies that home to the skin and have no known molecular basis for disease pathogenesis. Sézary syndrome (SS) is the leukemic variant of CTCL. Currently, CTCL is incurable, highlighting the need for new therapeutic modalities. We have previously observed that combined small-molecule inhibition of protein kinase C-β (PKCβ) and glycogen synthase kinase 3 (GSK3) causes synergistic apoptosis in CTCL cell lines and patient cells. Through microarray analysis of a SS cell line, we surveyed global gene expression following combined PKCβ-GSK3 treatment to elucidate therapeutic targets responsible for cell death. Clinically relevant targets were defined as genes differentially expressed in SS patients that were modulated by combination-drug treatment of SS cells. Gene set enrichment analysis uncovered candidate genes enriched for an immune-cell signature, specifically the T-cell receptor and mitogen-activated protein kinase signaling pathways. Further analysis identified p38 as a potential therapeutic target that is overexpressed in SS patients and decreased by synergistic-inhibitor treatment. This target was verified through small-molecule inhibition of p38, leading to cell death in both SS cell lines and patient cells. These data establish p38 as a SS biomarker and a potential therapeutic target for the treatment of CTCL.

Show MeSH
Related in: MedlinePlus