Novel cell adhesion/migration pathways are predictive markers of HDAC inhibitor resistance in cutaneous T cell lymphoma

Abstract

Background Treatment for Cutaneous T Cell Lymphoma (CTCL) is generally not curative. Therefore, selecting therapy that is effective and tolerable is critical to clinical decision-making. Histone deacetylase inhibitors (HDACi), epigenetic modifier drugs, are commonly used but effective in only ~30% of patients. There are no predictive markers of HDACi response and the CTCL histone acetylation landscape remains unmapped. We sought to identify pre-treatment molecular markers of resistance in CTCL that progressed on HDACi therapy. Methods Purified T cells from 39 pre/post-treatment peripheral blood samples and skin biopsies from 20 patients were subjected to RNA-seq and ChIP-seq for histone acetylation marks (H3K14/9 ac, H3K27ac). We correlated significant differences in histone acetylation with gene expression in HDACi-resistant/sensitive CTCL. We extended these findings in additional CTCL patient cohorts (RNA-seq, microarray) and using ELISA in matched CTCL patient plasma. Findings Resistant CTCL exhibited high levels of histone acetylation, which correlated with increased expression of 338 genes (FDR < 0·05), including some novel to CTCL: BIRC5 (anti-apoptotic); RRM2 (cell cycle); TXNDC5 , GSTM1 (redox); and CXCR4 , LAIR2 (cell adhesion/migration). Several of these, including LAIR2 , were elevated pre-treatment in HDACi-resistant CTCL. In CTCL patient plasma ( n = 6), LAIR2 protein was also elevated ( p < 0·01) compared to controls. Interpretation This study is the first to connect genome-wide differences in chromatin acetylation and gene expression to HDACi-resistance in primary CTCL. Our results identify novel markers with high pre-treatment expression, such as LAIR2, as potential prognostic and/or predictors of HDACi-resistance in CTCL. Funding NIH:CA156690, CA188286; NCATS: WU-ICTS UL1 TR000448; Siteman Cancer Center: CA091842.

Gene Expression Comparison between Sézary Syndrome and Lymphocytic-Variant Hypereosinophilic Syndrome Refines Biomarkers for Sézary Syndrome

“…Showe et al [112] first described the loss of STAT4 expression in SS PBMCs, and Litvinov et al [113] confirmed that low STAT4 expression in CTCL lesional skin is associated with progressive disease. However, in a separate study, higher STAT4 expression was associated with HDACi resistance in MF/SS patients [114], suggesting that alternative pathways to malignancy may be active in these patients.…”

Epigenetics of cutaneous T-cell lymphoma: biomarkers and therapeutic potentials

“…Precise predictive indicators for therapeutic responses are a recognized unmet need 140 . Downregulated expression of the BCL11B gene 159 , overexpression of LAIR2 160 , or recurrent genetic alterations ( RAD23B copy number loss and STAT3 Y640F variant 161 ) have been reported as potential indicators of HDACi resistance in laboratory investigations. Using the assay for transposase-accessible chromatin sequencing (ATAC-seq) that can map the open chromatin sites throughout the genome, a seminal study indicated that only patients who responded well to HDACis showed a gain of chromatin accessibility in CTCL cells after treatment 162 , 163 .…”

Novel targeted therapies of T cell lymphomas

“…Recently, Andrews et al . [ 48 ] showed differences in the acetylation levels of gene regulatory elements between HDACi-sensitive and HDACi-resistant CTCL patients. These changes were linked to the different expression of genes involved in the cell cycle, apoptosis, cytokine/chemokine signaling, and cell adhesion/migration pathways.…”

“…These changes were linked to the different expression of genes involved in the cell cycle, apoptosis, cytokine/chemokine signaling, and cell adhesion/migration pathways. In HDACi-resistant samples, increased acetylation was particularly significant near potential MF/SS oncogenes CCR6, CXCR4, and LAIR2 [ 48 ]. The last one was suggested to be used as an HDACi-resistant marker.…”