Chronic lymphocytic leukemia: molecular heterogeneity revealed by high-throughput genomics

Abstract

Chronic lymphocytic leukemia (CLL) has been consistently at the forefront of genetic research owing to its prevalence and the accessibility of sample material. Recently, genome-wide technologies have been intensively applied to CLL genetics, with remarkable progress. Single nucleotide polymorphism arrays have identified recurring chromosomal aberrations, thereby focusing functional studies on discrete genomic lesions and leading to the first implication of somatic microRNA disruption in cancer. Next-generation sequencing (NGS) has further transformed our understanding of CLL by identifying novel recurrently mutated putative drivers, including the unexpected discovery of somatic mutations affecting spliceosome function. NGS has further enabled in-depth examination of the transcriptional and epigenetic changes in CLL that accompany genetic lesions, and has shed light on how different driver events appear at different stages of disease progression and clonally evolve with relapsed disease. In addition to providing important insights into disease biology, these discoveries have significant translational potential. They enhance prognosis by highlighting specific lesions associated with poor clinical outcomes (for example, driver events such as mutations in the splicing factor subunit gene SF3B1) or with increased clonal heterogeneity (for example, the presence of subclonal driver mutations). Here, we review new genomic discoveries in CLL and discuss their possible implications in the era of precision medicine.

Figure 1

In recent years, CLL has been investigated through the use of several novel genomic technologies. CLL is a disease of mature B cells that is typically present in high abundance in blood; a typical peripheral blood smear is shown in the top panel. The typical source material used for these studies is primary peripheral blood CLL samples. Four main genomic approaches have been applied to this disease, including whole-exome/genome DNA sequencing, SNP arrays for copy number measurement, RNA sequencing and analyses of DNA methylation. These studies have added a substantial amount of information regarding the biology of CLL. CLL, chronic lymphocytic leukemia; LOH, loss of heterozygosity; SNP, single nucleotide polymorphism.

Figure 2

Affected genes in CLL discovered through genomic sequencing studies can be grouped into seven core cellular pathways. Genes recurrently mutated in CLL samples are shown in red ovals, while genes found to be mutated in isolated samples but which did not reach statistical significance are shown as pink ovals. Affected cellular elements include four signaling pathways with a known role in B-cell biology: inflammatory pathways, B-cell receptor signaling, Notch signaling, and Wnt signaling. Notch and Wnt signaling both provide important pro-survival input for CLL cells, allowing them to evade apoptosis [115-117]. In addition, they serve as an important bridge with the microenvironment, which is of particular importance in CLL, as manifested by relatively poor cell survival outside of the endogenous niche (for example, in in vitro or in vivo animal models) [118]. BCR signaling and inflammatory pathways may serve similar functions, and in addition may form optimal early targets for somatic mutations as they hijack physiologically active cellular pathways in relatively differentiated B cells [75,119]. In addition, three intranuclear processes are involved, including DNA repair, chromatic modification and RNA processing. Although the role of DNA repair disruptions has been extensively investigated, with multiple effects on pro-survival circuits, growth and genetic plasticity [120,121], the role of the other two intranuclear processes remains to be fully elucidated in CLL. IC, intracellular; C, cytoplasm.