| Literature DB >> 30537513 |
Duohui Jing1, Yizhou Huang2, Xiaoyun Liu3, Keith C S Sia3, Julia C Zhang3, Xiaolu Tai4, Meng Wang4, Cara E Toscan3, Hannah McCalmont3, Kathryn Evans3, Chelsea Mayoh3, Rebecca C Poulos5, Miriam Span3, Jianqing Mi6, Chao Zhang4, Jason W H Wong5, Dominik Beck2, John E Pimanda7, Richard B Lock8.
Abstract
Glucocorticoids play a critical role in the treatment of lymphoid malignancies. While glucocorticoid efficacy can be largely attributed to lymphocyte-specific apoptosis, its molecular basis remains elusive. Here, we studied genome-wide lymphocyte-specific open chromatin domains (LSOs), and integrated LSOs with glucocorticoid-induced RNA transcription and chromatin modulation using an in vivo patient-derived xenograft model of acute lymphoblastic leukemia (ALL). This led to the identification of LSOs critical for glucocorticoid-induced apoptosis. Glucocorticoid receptor cooperated with CTCF at these LSOs to mediate DNA looping, which was inhibited by increased DNA methylation in glucocorticoid-resistant ALL and non-lymphoid cell types. Our study demonstrates that lymphocyte-specific epigenetic modifications pre-determine glucocorticoid resistance in ALL and may account for the lack of glucocorticoid sensitivity in other cell types.Entities:
Keywords: acute lymphoblastic leukemia; chromatin accessibility; drug resistance; enhancer; epigenetics; glucocorticoid; lymphocyte specificity; patient-derived xenograft, PDX
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Year: 2018 PMID： 30537513 DOI： 10.1016/j.ccell.2018.11.002
Source DB: PubMed Journal: Cancer Cell ISSN： 1535-6108 Impact factor: 31.743