Advances in Epigenetics and Epigenomics in Chronic Lymphocytic Leukemia

Current Genetic Medicine Reports (2019) 7:214–226 https://doi.org/10.1007/s40142-019-00178-3 EPIGENETICS AND EPIGENOMICS (C BELL, SECTION EDITOR) Advances in Epigenetics and Epigenomics in Chronic Lymphocytic Leukemia Charalampos Xanthopoulos 1 & Efterpi Kostareli 1 Published online: 27 November 2019 # The Author(s) 2019 Abstract Purpose of Review The development and progression of chronic lymphocytic leukemia (CLL), a highly heterogenous B cell malignancy, are influenced by both genetic and environmental factors. Environmental factors, including pharmacological interventions, can affect the epigenetic landscape of CLL and thereby determine the CLL phenotype, clonal evolution, and clinical outcome. In this review, we critically present the latest advances in the field of CLL epigenomics/epigenetics in order to provide a systematic overview of to-date achievements and highlight the potential of epigenomics approaches in light of novel treatment therapies. Recent Findings Recent technological advances have enabled broad and precise mapping of the CLL epigenome. The identification of CLL-specific DNA methylation patterns has allowed for accurate CLL subtype definition, a better understanding of clonal origin and evolution, and the discovery of reliable biomarkers. More recently, studies have started to unravel the prognostic, predictive, and therapeutic potential of mapping chromatin dynamics and histone modifications in CLL. Finally, analysis of non-coding RNA expression has indicated their contribution to disease pathogenesis and helped to define prognostic subsets in CLL. Summary Overall, the potential of CLL epigenomics for predicting treatment response and resistance is mounting, especially with the advent of novel targeted CLL therapies. Keywords Chronic lymphocytic leukemia (CLL) . Epigenetics . Epigenomics . DNA methylation . Histone modifications . Chromatin . Non-coding RNAs Introduction Chronic lymphocytic leukemia (CLL), the most common adult leukemia in the Western world, is viewed as a disease with immense heterogeneity at the clinical, cellular, and molecular levels. A multitude of studies have provided insight on how CLL clinical heterogeneity can be reflected on epigenetic signatures at the DNA methylation, histone modifications, and non-coding RNAs levels. Epigenetic patterns can alter as a response to changes in This article is part of the Topical Collection on Epigenetics and Epigenomics Electronic supplementary material The online version of this article (https://doi.org/10.1007/s40142-019-00178-3) contains supplementary material, which is available to authorized users. * Efterpi Kostareli 1 The Wellcome-Wolfson Institute for Experimental Medicine, Queen’s University Belfast, 97 Lisburn Road, Belfast BT9 7BL, UK the (micro)environment, including antigenic stimulus, cross-talk with other cells, exposure to soluble factors at CLL niche, or as a result of pharmacological interventions. Investigating epigenetics and epigenomics can offer not only valuable insights into cell ontogeny and disease pathogenesis but into underlying mechanisms for clinical and molecular heterogeneity. Furthermore, identification of epigenetic signatures via epigenome-wide approaches can assist the shift towards a precision-medicine model for disease management [1, 2]. Previous research summaries have documented the key scientific approaches around the CLL epigenome [3, 4]. In this review, we highlight recent advances in CLL epigenetics and epigenomics with a focus on translational potential of key genes/regions, as biomarkers or drug targets (Fig. 1). DNA Methylation Over the last decade, a large body of experimental data has documented that DNA methylation plays variable functional roles linked to CLL pathogenesis and disease outcome. Our Curr Genet Med Rep (2019) 7:214–226 Fig. 1 Overview of CLL epigenetics. Microenvironmental signals shape to a critical point CLL B cell fate and B cell receptor (BCR) possess a central role into this translational process. A significant number of proteins have been reported to be regulated by DNA methylation in CLL. For instance, ZAP70, TP63, NFATc1, and others (dark grey boxes) have been found to be upregulated by DNA hypomethylation (promoter/gene body/cis-regulation) either in CLL as a whole or only in specific CLL subsets with diverse prognosis. Other molecules such as KLF4, DUSP22, and various miRs were downregulated and epigenetically silenced via DNA promoter hypermethylation or gene body/cis-regulatory element DNA methylation changes (light yellow boxes). Furthermore, molecules expressed either in the cytoplasm or in the nucleus such as tumor suppressive microRNAs (i.e., miR-708), long non-coding RNAs (i.e., CRNDE) and histone-modifying enzymes (HME) (i.e., EZH2) have been found to be epigenetically dysregulated in CLL. These molecules act as epigenetic regulators and are either downregulated or aberrantly overexpressed affecting the downstream signaling cascade, the epigenome and transcriptome. Interestingly, aberrant expression and function of various factors have been found to be actively mediated by HDACs (black boxes) or EZH2 enzymes (light grey boxes). Through a dynamic process, HMEs (HDAC, EZH2, SETD2, CHD2 and KDM4) can alter chromatin configuration and TF dependencies for regulatory areas (i.e., promoters, enhancers). These epigenetic changes are the catalytic switch for enabling or blocking gene transcription and not surprisingly, HME inhibition has shown to be the most promising strategy of epigenetic therapy in CLL. The figure was created with BioRender.com. AP-1, activator protein 1; BTK, Bruton’s tyrosine kinase; BCR, B cell receptor; CHD2, 215 chromodomain helicase DNA-binding protein 2; CLL, chronic lymphocytic leukemia; CRNDE, colorectal neoplasia differentially expressed; CD20, B-lymphocyte antigen CD20; CRC, core regulatory circuit; DNMT, DNA methyltransferase; DUSP22, dual specificity phosphatase 22; EBF1, early B cell factor 1; EZH2, enhancer of zeste homolog 2; FOX, forkhead box; HDAC, histone deacetylase; H3K27me3, histone H3 trimethylation at lysine 27; H3K4me3, histone H3 trimethylation at lysine 4; H3K9ac, histone H3 acetylation at lysine 9; H3K9me3 histone H3 trimethylation at lysine 9; H3K27ac, histone H3 acetylation at lysine 27; IL10, interleukin 10; IGF1R, insulin-like growth factor 1 receptor; IKKb, IκB-kinase β; IP3, inositol 1,4,5-triphosphate; KDM4, histone lysine demethylase subfamily 4; LEF, lymphoid enhancer-binding factor; M-CLL, IGHV-mutated CLL subset; MCPH1, microcephalin; MEK/ERK, mitogen-activated protein kinase/ extracellular receptor kinase pathway; miR, microRNA; MYC, oncogene carried by the Avian virus, myelocytomatosis; NFATC1, nuclear factor of activated T cells, cytoplasmic 1; NF-κΒ, nuclear factor kappa-light-chain-enhancer of activated B cells; NOTCH, neurogenic locus notch homolog protein; PAX5, paired box protein Pax-5; PI3K/AKT pathway, phosphoinositide 3-kinase/AK (...truncated)