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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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Clinical relevance of drug-induced genomic changes are supported by SS patient microarray dataA gene expression signature for CTCL patients was derived using publically available data sets from SS patients and healthy donor CD4+ cells. (a) Hierarchical clustering of patient and healthy donors (b) SS patient sample gene expression signature shares pathways with Hut78 drug treatment microarray signature. Black bars highlight TCR and MAPK signaling pathways. (c) Number of genes with expression negatively correlated between SS patients and drug treated SS cells.
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Figure 2: Clinical relevance of drug-induced genomic changes are supported by SS patient microarray dataA gene expression signature for CTCL patients was derived using publically available data sets from SS patients and healthy donor CD4+ cells. (a) Hierarchical clustering of patient and healthy donors (b) SS patient sample gene expression signature shares pathways with Hut78 drug treatment microarray signature. Black bars highlight TCR and MAPK signaling pathways. (c) Number of genes with expression negatively correlated between SS patients and drug treated SS cells.

Mentions: To identify candidate genes that may have therapeutic importance and to further explore the clinical relevance of our drug-treatment data set, we interrogated the gene expression profile of a set of SS patients (GSE17602; (Caprini et al. 2009)) normalized to normal CD4+ T-cells (GSE8835; (Görgün et al. 2005)) using methods described previously in this paper. Hierarchical clustering was performed for the 3,354 differentially modulated genes in SS patients. A total of 1,696 genes were up-regulated while 1,658 were genes were down-regulated in patients (Figure 2a). GSEA was performed, and, of the top 100 pathways with significant enrichment in our patient data set (q<0.05), 17 pathways were shared with the combination-drug treatment signature (Figure 2b and Supplemental Table S2, online). TCR and MAPK signaling pathways were enriched in both data sets (graphical representation of genes modulated, Supplemental Figure S4, online). To further refine our candidate genes to those with clinical relevance for target identification, we selected genes with expression negatively correlated between patients and drug treated cell lines. Eighty-nine genes were simultaneously up-regulated in SS patients and down-regulated by combination-drug treatment; 34 genes were down-regulated in SS patients and up-regulated by Enz+ARA treatment (Figure 2c, Supplemental Tables S3 and S4, online). Of the shared genes, several were associated with the TCR pathway and immune system signaling. In particular, MAPK11 (p38β) showed significant correlation with overexpression in SS patients and down-regulation by combination-drug treatment (SS, FC=3.5473; Enz+ARA, FC=0.4991).


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)

Clinical relevance of drug-induced genomic changes are supported by SS patient microarray dataA gene expression signature for CTCL patients was derived using publically available data sets from SS patients and healthy donor CD4+ cells. (a) Hierarchical clustering of patient and healthy donors (b) SS patient sample gene expression signature shares pathways with Hut78 drug treatment microarray signature. Black bars highlight TCR and MAPK signaling pathways. (c) Number of genes with expression negatively correlated between SS patients and drug treated SS cells.
© Copyright Policy
Related In: Results  -  Collection

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

Figure 2: Clinical relevance of drug-induced genomic changes are supported by SS patient microarray dataA gene expression signature for CTCL patients was derived using publically available data sets from SS patients and healthy donor CD4+ cells. (a) Hierarchical clustering of patient and healthy donors (b) SS patient sample gene expression signature shares pathways with Hut78 drug treatment microarray signature. Black bars highlight TCR and MAPK signaling pathways. (c) Number of genes with expression negatively correlated between SS patients and drug treated SS cells.
Mentions: To identify candidate genes that may have therapeutic importance and to further explore the clinical relevance of our drug-treatment data set, we interrogated the gene expression profile of a set of SS patients (GSE17602; (Caprini et al. 2009)) normalized to normal CD4+ T-cells (GSE8835; (Görgün et al. 2005)) using methods described previously in this paper. Hierarchical clustering was performed for the 3,354 differentially modulated genes in SS patients. A total of 1,696 genes were up-regulated while 1,658 were genes were down-regulated in patients (Figure 2a). GSEA was performed, and, of the top 100 pathways with significant enrichment in our patient data set (q<0.05), 17 pathways were shared with the combination-drug treatment signature (Figure 2b and Supplemental Table S2, online). TCR and MAPK signaling pathways were enriched in both data sets (graphical representation of genes modulated, Supplemental Figure S4, online). To further refine our candidate genes to those with clinical relevance for target identification, we selected genes with expression negatively correlated between patients and drug treated cell lines. Eighty-nine genes were simultaneously up-regulated in SS patients and down-regulated by combination-drug treatment; 34 genes were down-regulated in SS patients and up-regulated by Enz+ARA treatment (Figure 2c, Supplemental Tables S3 and S4, online). Of the shared genes, several were associated with the TCR pathway and immune system signaling. In particular, MAPK11 (p38β) showed significant correlation with overexpression in SS patients and down-regulation by combination-drug treatment (SS, FC=3.5473; Enz+ARA, FC=0.4991).

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