Integrative epigenomics in chronic lymphocytic leukaemia: Biological insights and clinical applications

Abstract

Summary Chronic lymphocytic leukaemia (CLL) is not only characterised by driver genetic alterations but by extensive epigenetic changes. Over the last decade, epigenomic studies have described the DNA methylome, chromatin accessibility, histone modifications and the three‐dimensional (3D) genome architecture of CLL. Beyond its regulatory role, the DNA methylome contains imprints of the cellular origin and proliferative history of CLL cells. These two aspects are strong independent prognostic factors. Integrative analyses of chromatin marks have uncovered novel regulatory elements and altered transcription factor networks as non‐genetic means mediating gene deregulation in CLL. Additionally, CLL cells display a disease‐specific pattern of 3D genome interactions. From the technological perspective, we are currently witnessing a transition from bulk omics to single‐cell analyses. This review aims at summarising the major findings from the epigenomics field as well as providing a prospect of the present and future of single‐cell analyses in CLL.

Chronic Lymphocytic Leukemia (CLL) with Borderline Immunoglobulin Heavy Chain Mutational Status, a Rare Subgroup of CLL with Variable Disease Course

“…Indeed, from our and previous studies, the association of different biological predictors with a BL-IGHV mutational status starts to emerge, depicting a subgroup of CLL frequently harboring del(11q), low rates of NOTCH1 mutations, biased usage of specific IGHV genes and an enrichment in subset #2 cases. Moreover, DNA methylation studies recently identified a distinct clinico-biological CLL subgroup, termed intermediate-CLL, characterized by moderately mutated IGHV genes (95–98% identity to the germline sequence), enrichment in subset #2 cases, SF3B1 mutations, and an intermediate TTFT with relatively favorable OS [ 46 , 47 , 48 ]. Intermediate-CLL finds its postulated cellular origin in a germinal center-experienced B-cell that has undergone early selection through the germinal center reaction, thus retaining both an intermediate methylation program and a somatic hypermutation burden that falls in the BL-IGHV range [ 47 ].…”

“…Moreover, DNA methylation studies recently identified a distinct clinico-biological CLL subgroup, termed intermediate-CLL, characterized by moderately mutated IGHV genes (95–98% identity to the germline sequence), enrichment in subset #2 cases, SF3B1 mutations, and an intermediate TTFT with relatively favorable OS [ 46 , 47 , 48 ]. Intermediate-CLL finds its postulated cellular origin in a germinal center-experienced B-cell that has undergone early selection through the germinal center reaction, thus retaining both an intermediate methylation program and a somatic hypermutation burden that falls in the BL-IGHV range [ 47 ]. While awaiting confirmatory studies, these findings could represent the first seminal evidence suggesting that BL-IGHV mutated CLL might have superimposable biological characteristics to intermediate methylated CLL.…”

Treatment of Chronic Lymphocytic Leukemia in the Personalized Medicine Era

“…Approximately 80% of patients have genetic mutations for del(13q), del(11q), del(17p), or trisomy 12. In contrast, a smaller percentage of patients, around 10–20%, have a more heterogeneous low-frequency mutation profile [ 15 ]. Massive sequencing techniques have identified several mutations in different genes, with an average of 20 specific mutations detected per case of CLL, which is considered relatively low in relation to other tumors.…”

“…Certain factors contributing to this include the presence of an IGHVum gene, cytogenetic abnormalities like a complex karyotype, del(17p), TP53mut, and others. The temporal aspect of disease progression also stands as a crucial prognostic element in relapsed CLL patients [ 15 ].…”

Prognostic Value of the miR-17~92 Cluster in Chronic Lymphocytic Leukemia

“…CLL displays a heterogeneous spectrum of biological features and clinical manifestations. Due to clinical interindividual heterogeneity of CLL cases, identification of prognostic factors is of great importance in both predicting the course of the disease as well as selecting the optimal therapy [ 1 , 2 , 3 , 4 ].…”