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Semin Cancer Biol. 2018 Aug;51:1-11. doi: 10.1016/j.semcancer.2018.02.001. Epub 2018 Feb 7.

Epigenetic deregulation in chronic lymphocytic leukemia: Clinical and biological impact.

Author information

1
Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Sweden; Department of Molecular Medicine and Surgery, Karolinska Institutet, Sweden.
2
Division of Epigenomics and Cancer Risk Factors, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.
3
Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Sweden; Department of Molecular Medicine and Surgery, Karolinska Institutet, Sweden. Electronic address: richard.rosenquist@ki.se.

Abstract

Deregulated transcriptional control caused by aberrant DNA methylation and/or histone modifications is a hallmark of cancer cells. In chronic lymphocytic leukemia (CLL), the most common adult leukemia, the epigenetic 'landscape' has added a new layer of complexity to our understanding of this clinically and biologically heterogeneous disease. Early studies identified aberrant DNA methylation, often based on single gene promoter analysis with both biological and clinical impact. Subsequent genome-wide profiling studies revealed differential DNA methylation between CLLs and controls and in prognostics subgroups of the disease. From these studies, it became apparent that DNA methylation in regions outside of promoters, such as enhancers, is important for the regulation of coding genes as well as for the regulation of non-coding RNAs. Although DNA methylation profiles are reportedly stable over time and in relation to therapy, a higher epigenetic heterogeneity or 'burden' is seen in more aggressive CLL subgroups, albeit as non-recurrent 'passenger' events. More recently, DNA methylation profiles in CLL analyzed in relation to differentiating normal B-cell populations revealed that the majority of the CLL epigenome reflects the epigenomes present in the cell of origin and that only a small fraction of the epigenetic alterations represents truly CLL-specific changes. Furthermore, CLL patients can be grouped into at least three clinically relevant epigenetic subgroups, potentially originating from different cells at various stages of differentiation and associated with distinct outcomes. In this review, we summarize the current understanding of the DNA methylome in CLL, the role of histone modifying enzymes, highlight insights derived from animal models and attempts made to target epigenetic regulators in CLL along with the future directions of this rapidly advancing field.

KEYWORDS:

Chronic lymphocytic leukemia; DNA methylation; Histone modification; Outcome; Prognosis

PMID:
29427646
DOI:
10.1016/j.semcancer.2018.02.001
[Indexed for MEDLINE]

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