期刊
CANCER CELL
卷 34, 期 6, 页码 906-+出版社
CELL PRESS
DOI: 10.1016/j.ccell.2018.11.002
关键词
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资金
- Anthony Rothe Memorial Trust [RRE/0700:bm]
- Priority-Driven Collaborative Cancer Research Scheme [1129129]
- Cancer Institute NSW
- Balnaves Foundation (Young Researchers Fund)
- National Health and Medical Research Council of Australia (NHMRC Fellowship) [APP1059804]
- NHMRC [1042934, 1102589]
- Cancer Australia
- Kids' Cancer Project
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.
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