Lymphocyte-Specific Chromatin Accessibility Pre-determines Glucocorticoid Resistance in Acute Lymphoblastic Leukemia
| Autor: | Jing, D, Huang, Y, Liu, X, Sia, KCS, Zhang, JC, Tai, X, Wang, M, Toscan, CE, McCalmont, H, Evans, K, Mayoh, C, Poulos, RC, Span, M, Mi, J, Zhang, C, Wong, JWH, Beck, D, Pimanda, JE, Lock, RB |
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| Rok vydání: | 2018 |
| Předmět: |
Mice
Knockout Apoptosis Mice SCID Precursor Cell Lymphoblastic Leukemia-Lymphoma Xenograft Model Antitumor Assays Chromatin Dexamethasone Mice Inbred NOD Drug Resistance Neoplasm Antineoplastic Combined Chemotherapy Protocols Azacitidine Animals Humans Oncology & Carcinogenesis Lymphocytes Glucocorticoids hormones hormone substitutes and hormone antagonists |
| Popis: | © 2018 Elsevier Inc. 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. Jing et al. identified lymphocyte-specific open chromatin domains (LSOs) critical for glucocorticoid (GC)-induced acute lymphoblastic leukemia (ALL) apoptosis. GC receptor cooperated with CTCF at these LSOs to mediate DNA looping, which was inhibited by DNA methylation in GC-resistant ALL and non-lymphoid cell types. |
| Databáze: | OpenAIRE |
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