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.

FISHing in the dark: How the combination of FISH and conventional karyotyping improves the diagnostic yield in CpG‐stimulated chronic lymphocytic leukemia

“…The emergence of CpG-ODN-oligonucleotides (CpG-ODN), a potent B-cell mitogen, has enhanced our ability to reproducibly detect clonal cytogenetic aberrations by karyotyping, expanding our understanding of clinically relevant cytogenetic aberrations [15][16][17][18]. Array-based profiling and, more recently, next-generation sequencing have identified recurrent genomic imbalances [19] and highlighted the importance of subclonal genomic lesions (i.e., intratumoral heterogeneity) [20]. While promising, these methodologies have yet to be readily utilized by diagnostic laboratories, which largely rely on the CLL FISH panel alone.…”

Novel prognostic molecular factors: a quantum leap in the field of chronic lymphocytic leukemia

“…Consequently, the BIRC3 mutation is associated with shorter PFS and OS [12,63,85]. There are reports which attribute the presence of the mutation to chemorefractoriness [83,86,87]. In the study of Landau et al [86], 24% of patients who were refractory to fludarabine-therapy harbored mutated BIRC3 gene.…”

“…There are reports which attribute the presence of the mutation to chemorefractoriness [83,86,87]. In the study of Landau et al [86], 24% of patients who were refractory to fludarabine-therapy harbored mutated BIRC3 gene. BIRC3 mutations are rarely described in patients at diagnosis of CLL accounting from 2 to 10% [85][86][87][88].…”

“…In the study of Landau et al [86], 24% of patients who were refractory to fludarabine-therapy harbored mutated BIRC3 gene. BIRC3 mutations are rarely described in patients at diagnosis of CLL accounting from 2 to 10% [85][86][87][88]. They might be detected between exons 2 and 9 [87].…”

The Endothelial Nitric Oxide Synthase Gene Variants as a Risk Factor for Chronic Lymphocytic Leukemia

“…1,2 The precise pathogenesis of CLL is still unknown. However genetic, environmental and immunological factors have been offered to account for the development of CLL.…”