Details

Autor(en) / Beteiligte

• Jing, Duohui
• Huang, Yizhou
• Liu, Xiaoyun
• Sia, Keith C.S.
• Zhang, Julia C.
• Tai, Xiaolu
• Wang, Meng
• Toscan, Cara E.
• McCalmont, Hannah
• Evans, Kathryn
• Mayoh, Chelsea
• Poulos, Rebecca C.
• Span, Miriam
• Mi, Jianqing
• Zhang, Chao
• Wong, Jason W.H.
• Beck, Dominik
• Pimanda, John E.
• Lock, Richard B.

Titel

Lymphocyte-Specific Chromatin Accessibility Pre-determines Glucocorticoid Resistance in Acute Lymphoblastic Leukemia

Ist Teil von

• Cancer cell, 2018-12, Vol.34 (6), p.906-921.e8

Ort / Verlag

United States: Elsevier Inc

Erscheinungsjahr

2018

Link zum Volltext

Quelle

EZB Electronic Journals Library

Beschreibungen/Notizen

• 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. [Display omitted] •Identified open chromatin domains associated with glucocorticoid response in ALL•Glucocorticoid-resistant ALL shows abnormal accessibility at GR-bound enhancers•GR and CTCF bind at a lymphocyte-specific enhancer for BIM to mediate DNA looping•The BIM enhancer is highly methylated in resistant ALL and non-lymphoid 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.