Evolving understanding of the CLL genome

Abstract

Over the past few years, massively parallel sequencing technologies have revealed with high resolution the tremendous genetic and epigenetic heterogeneity in chronic lymphocytic leukemia (CLL). We have learned how the molecular architecture differs not only between affected individuals but also within samples and over time. These insights have catalyzed our understanding of the pathobiology of CLL and point to critical signaling pathways in the development and progression of the disease. Several key driver alterations have been identified, which serve to refine prognostic schemata but also to inspire the development of new therapeutic strategies. Ongoing advances in technology promise to further elucidate the molecular basis of CLL, and this knowledge is anticipated to aid us in understanding and addressing the clinical challenge presented by the vast variability in the clinical course of patients with CLL.

Figure 1

Evolution and growth in our understanding of CLL heterogeneity over time.

Figure 2

Inter- and intraleukemic genetic (A, B) and epigenetic (C, D) heterogeneity in CLL revealed by next-generation sequencing. Panel A, B, C were adapted with permission from Wang et al, Landau et al, Kulis at al, respectively. Panel D was provided by Landau et al.

Figure 3

Frequency of genetic alterations in CLL depending on the cohort. The largest cohort per center has been taken into account, and the number of mutated cases over total size of the cohort is noted. Unselected cohorts have been included from: DFCI (Dana-Farber Cancer Institute)/Broad Institute,^, Italy (Amedeo Avogadro University of Eastern Piedmont, Novara; Sapienza University, Rome)/Columbia University,^,,,– MLL (Munich Leukemia Laboratory),^, SCALE (Scandinavian Lymphoma Etiology).^, Included are also cohorts from the clinical trials UK LRF (UK Lymphoma Research Foundation) CLL4,^, GCLLSG (German CLL Study Group) CLL4, GCLLSG CLL2H. “Early” - newly diagnosed and untreated patients without explicit evidence for progressive disease; “progressive” - patients with symptomatic CLL requiring treatment, or with relapse after treatment.

Figure 4

Recurrent putative driver alterations in mature B cell non-Hodgkin lymphomas. MCL -mantle cell lymphoma, FL - follicular lymphoma, BL - Burkitt’s lymphoma, DLBCL - diffuse large B cell lymphoma, SMZL - splenic marginal zone lymphoma, CLL, WM - Waldenström’s macroglobulinaemia and MM - multiple myeloma assessed by NGS (WGS - Whole Genome Sequencing, WES - Whole Exome Sequencing, TS - Targeted Sequencing [NGS or Sanger Sequencing], RNAseq, or SNP array). Shown are all alterations that were significant in CLL in at least one study. For alterations in other entities, selected ones have been validated and occurred in a significant and high proportion (>10% of cases) in at least one study, or were identified across independent studies and were significant in at least one study.