Meghan Bliss-Moreau, Cristian Coarfa, Preethi H

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Identification of p38β as a Therapeutic Target for the Treatment of Sézary Syndrome Meghan Bliss-Moreau, Cristian Coarfa, Preethi H. Gunaratne, Joan Guitart, Nancy L. Krett, Steven T. Rosen Journal of Investigative Dermatology Volume 135, Issue 2, Pages 599-608 (February 2015) DOI: 10.1038/jid.2014.367 Copyright © 2015 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 1 Combined small-molecule microarray analysis and results. Global gene expression analysis was performed on Hut78 cells treated for 3 days with Enzastaurin (Enz), AR-A014418 (ARA), and Enz+ARA. DMSO (vehicle) or no treatment cells served as controls. Four serial replicates were collected. (a) Venn diagrams of up- and downregulated 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. Gene set enrichment analysis (GSEA) was performed on combination-treatment gene signature (1,807 total). TCR signaling, downstream p38α/β signaling, and nuclear β-catenin signaling pathways were enriched post Enz+ARA treatment. Journal of Investigative Dermatology 2015 135, 599-608DOI: (10.1038/jid.2014.367) Copyright © 2015 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 2 Clinical relevance of drug-induced genomic changes are supported by Sézary syndrome (SS) patient microarray data. A gene expression signature for cutaneous T-cell lymphoma (CTCL) patients was derived using publically available data sets from SS patients and healthy donor CD4+ cells. (a) Hierarchical clustering of patients and healthy donors (b) SS patient sample gene expression signature shares pathways with Hut78 drug treatment microarray signature. Black bars highlight TCR and mitogen-activated protein kinase (MAPK) signaling pathways. (c) A number of genes with expression negatively correlated between SS patients and drug-treated SS cells. Journal of Investigative Dermatology 2015 135, 599-608DOI: (10.1038/jid.2014.367) Copyright © 2015 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 3 Sézary syndrome (SS) cell lines and patient samples express all p38 isoforms. p38β (mitogen-activated protein kinase 11 (MAPK11)) is differentially regulated by small-molecule inhibitor treatment. (a,b) H9 and Hut78 cells were treated with Enzastaurin (Enz) and AR-A014418 (ARA) as previously described, n=3. (a) MAPK14, MAPK11, MAPK12, and MAPK13 mRNA expression measured by quantitative real-time reverse-transcriptase–PCR (qRT-PCR). (b) p38 isoform protein expression, normalized to α-tubulin, was measured by immunoblot. Representative immunoblot images of three replicates (quantification, Supplementary Figure 5 online). (c,d) Endogenous cutaneous T-cell lymphoma (CTCL) patient and healthy donor cell samples. (c) MAPK isoform mRNA expression measured by qRT-PCR, normalized to housekeeping genes, and normalized to donor cells. (d) Quantitative representation of p38 isoform immunoblots. Protein expression normalized to loading control (α-tubulin) expression and then normalized to healthy volunteers. H9/Hut78 cells as positive controls. Journal of Investigative Dermatology 2015 135, 599-608DOI: (10.1038/jid.2014.367) Copyright © 2015 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 4 In Sézary syndrome (SS) cell lines, inhibition of p38 with small molecules induces apoptosis, and BIRB796 works through a p38 mechanism. (a) H9 and Hut78 cells were treated with increasing concentrations of either SB202, SB203, or BIRB. Apoptosis was measured by flow cytometry, n=3. (b,c) H9 and Hut78 cells were cultured with either Enzastaurin (Enz)+AR-A014418 (ARA) plus BIRB or increasing concentrations of BIRB alone for 5 days. (b–d) Apoptosis was measured by Annexin V staining, n=3. Total cell death is represented as a fold change (FC) normalized to DMSO, in the absence of BIRB treatment. Comparisons were made between cells treated with BIRB alone and those treated with BIRB in the presence of Enz+ARA. (b) H9, (c) Hut78, (d), raw cell death (Annexin V–positive cells), and no BIRB treatment. Journal of Investigative Dermatology 2015 135, 599-608DOI: (10.1038/jid.2014.367) Copyright © 2015 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 5 Importance of p38 signaling in primary Sézary syndrome (SS) patient samples. (a–c) Peripheral blood mononuclear cells (PBMCs) were harvested from SS patients (n=3) and healthy volunteers (n=5) and treated with increasing concentrations of either SB202, SB203, or BIRB. Cell death was assessed by flow cytometry. Annexin V staining, positive stained cells quantified as percentage total PBMCs (for gating examples see Supplementary Figure S7 online). (a) SB202, (b) SB203, and (c) BIRB. Journal of Investigative Dermatology 2015 135, 599-608DOI: (10.1038/jid.2014.367) Copyright © 2015 The Society for Investigative Dermatology, Inc Terms and Conditions