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

Autor:	Jing D; Children's Cancer Institute, Lowy Cancer Research Centre, UNSW, Sydney, NSW 2052, Australia. Electronic address: djing@ccia.unsw.edu.au., Huang Y; Lowy Cancer Research Centre and the Prince of Wales Clinical School, UNSW, Sydney, NSW 2052, Australia; Centre for Health Technologies, School of Biomedical Engineering and the School of Software, University of Technology, Sydney, NSW 2007, Australia., Liu X; Children's Cancer Institute, Lowy Cancer Research Centre, UNSW, Sydney, NSW 2052, Australia., Sia KCS; Children's Cancer Institute, Lowy Cancer Research Centre, UNSW, Sydney, NSW 2052, Australia., Zhang JC; Children's Cancer Institute, Lowy Cancer Research Centre, UNSW, Sydney, NSW 2052, Australia., Tai X; School of Life Sciences and Technology, Tongji University, Shanghai 200092, China., Wang M; School of Life Sciences and Technology, Tongji University, Shanghai 200092, China., Toscan CE; Children's Cancer Institute, Lowy Cancer Research Centre, UNSW, Sydney, NSW 2052, Australia., McCalmont H; Children's Cancer Institute, Lowy Cancer Research Centre, UNSW, Sydney, NSW 2052, Australia., Evans K; Children's Cancer Institute, Lowy Cancer Research Centre, UNSW, Sydney, NSW 2052, Australia., Mayoh C; Children's Cancer Institute, Lowy Cancer Research Centre, UNSW, Sydney, NSW 2052, Australia., Poulos RC; Lowy Cancer Research Centre and the Prince of Wales Clinical School, UNSW, Sydney, NSW 2052, Australia., Span M; Children's Cancer Institute, Lowy Cancer Research Centre, UNSW, Sydney, NSW 2052, Australia., Mi J; State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, Rui Jin Hospital Affiliated to School of Medicine, Shanghai Jiao Tong University, Shanghai 200025, China., Zhang C; School of Life Sciences and Technology, Tongji University, Shanghai 200092, China., Wong JWH; Lowy Cancer Research Centre and the Prince of Wales Clinical School, UNSW, Sydney, NSW 2052, Australia., Beck D; Lowy Cancer Research Centre and the Prince of Wales Clinical School, UNSW, Sydney, NSW 2052, Australia; Centre for Health Technologies, School of Biomedical Engineering and the School of Software, University of Technology, Sydney, NSW 2007, Australia., Pimanda JE; Lowy Cancer Research Centre and the Prince of Wales Clinical School, UNSW, Sydney, NSW 2052, Australia; Department of Haematology, Prince of Wales Hospital, Sydney, NSW 2210, Australia., Lock RB; Children's Cancer Institute, Lowy Cancer Research Centre, UNSW, Sydney, NSW 2052, Australia. Electronic address: rlock@ccia.unsw.edu.au.
Jazyk:	angličtina
Zdroj:	Cancer cell [Cancer Cell] 2018 Dec 10; Vol. 34 (6), pp. 906-921.e8.
DOI:	10.1016/j.ccell.2018.11.002
Abstrakt:	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. (Copyright © 2018 Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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