Chromatin Accessibility Landscape of Cutaneous T Cell Lymphoma and Dynamic Response to HDAC Inhibitors

• Published in: Cancer cell Vol. 32; no. 1; pp. 27 - 41.e4
• Main Authors: Qu, Kun, Zaba, Lisa C., Satpathy, Ansuman T., Giresi, Paul G., Li, Rui, Jin, Yonghao, Armstrong, Randall, Jin, Chen, Schmitt, Nathalie, Rahbar, Ziba, Ueno, Hideki, Greenleaf, William J., Kim, Youn H., Chang, Howard Y.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 10.07.2017
• Subjects: cancer epigenetics; Chromatin - chemistry; Chromatin - drug effects; Cluster Analysis; CTCL; Epigenomics; Gene Expression Regulation, Neoplastic; HDAC inhibitor; Histone Deacetylase Inhibitors - therapeutic use; Humans; Lymphoma, T-Cell, Cutaneous - drug therapy; Lymphoma, T-Cell, Cutaneous - genetics; response predictor; RNA, Messenger - metabolism; HDAC inhibitor; response predictor; cancer epigenetics; CTCL
• ISSN: 1535-6108; 1878-3686
• DOI: 10.1016/j.ccell.2017.05.008

Here, we define the landscape and dynamics of active regulatory DNA in cutaneous T cell lymphoma (CTCL) by ATAC-seq. Analysis of 111 human CTCL and control samples revealed extensive chromatin signatures that distinguished leukemic, host, and normal CD4+ T cells. We identify three dominant patterns of transcription factor (TF) activation that drive leukemia regulomes, as well as TF deactivations that alter host T cells in CTCL patients. Clinical response to histone deacetylase inhibitors (HDACi) is strongly associated with a concurrent gain in chromatin accessibility. HDACi causes distinct chromatin responses in leukemic and host CD4+ T cells, reprogramming host T cells toward normalcy. These results provide a foundational framework to study personal regulomes in human cancer and epigenetic therapy. [Display omitted] •Regulome signatures distinguish CTCL leukemic, CTCL host, and normal CD4+ T cells•CTCL regulomes show three dominant patterns of transcription factor activity•Specific chromatin dynamics are associated with clinical response to HDACi•HDACi accentuates pre-existing DNA access in CTCL leukemic and host CD4+ T cells Qu et al. show that the accessible chromatin landscape distinguishes leukemic from host T cells in cutaneous T cell lymphoma (CTCL) patients as well as T cells from healthy individuals. The clinical response of CTCL to HDAC inhibitors strongly associates with a concurrent gain in chromatin accessibility.