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From pathogenesis to treatment of chronic lymphocytic leukaemia

Nature Reviews Cancer volume 10, pages 37–50 (2010)Cite this article

Key Points

  • Chronic lymphocytic leukaemia (CLL) is the most common leukaemia in the Western world. It is characterized by the accumulation of small B lymphocytes that have a mature appearance.

  • Two subsets of CLL cases can be differentiated by the degree of somatic hypermutation (mutated and unmutated immunoglobulin heavy chain variable region (IGHV) genes) that have distinct clinical and biological behaviours.

  • Overall, more than 20% of CLL cases carry stereotyped B cell receptors, suggesting that common antigen(s) are recognized by CLL cells.

  • Clonal B cell populations with a CLL immunophenotype have been detected in 3.5% of healthy individuals (monoclonal B cell lymphocytosis; MBL). MBL is often a CLL precursor.

  • Approximately 80% of CLLs show aberrations in a few frequently affected chromosomal regions, including 13q14 (mir-15a and mir16-1), 11q23 (ataxia telangiectasia-mutated; ATM), trisomy 12 and 17p13 (TP53). Recurrent translocations are rare in CLL.

  • Global and gene-specific aberrant DNA methylation has been detected in CLL. Almost all sporadic CLL cases also show epigenetic silencing of death-associated protein kinase 1.

  • In lymphoid organs, CLL cells interact with and seem to shape their microenvironment, which consists of T cells, stromal cells and soluble factors. This interaction is emerging as a therapeutic target.

  • p53 plays a central part in our current understanding of why some patients fail to respond to chemotherapy.

  • The most powerful prognostic factors include 17p13 deletion, TP53 mutation, 11q23 deletion, IGHV mutation status, serum markers, clinical stage and age.

  • CLL may serve as a model of how microenvironmental stimuli, antigenic drive and epigenetic, as well as genetic, deregulation are combined in cancer pathogenesis.

Abstract

Chronic lymphocytic leukaemia (CLL) has several unique features that distinguish it from other cancers. Most CLL tumour cells are inert and arrested in G0/G1 of the cell cycle and there is only a small proliferative compartment; however, the progressive accumulation of malignant cells will ultimately lead to symptomatic disease. Pathogenic mechanisms have been elucidated that involve multiple external (for example, microenvironmental stimuli and antigenic drive) and internal (genetic and epigenetic) events that are crucial in the transformation, progression and evolution of CLL. Our growing understanding of CLL biology is allowing the translation of targets and biological classifiers into clinical practice.

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Figure 1: CLL pathogenic mechanisms and examples of targeted treatment options.
Figure 2: CLLs with unmutated or mutated IGHV genes show markedly different biological and clinical behaviours.
Figure 3: TP53 mutations in CLL.

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Acknowledgements

We acknowledge the important contributions of the numerous researchers whose work could not be cited due to space restrictions. The authors are supported in part by the German José Carreras Leukemia Foundation (R06/28v, R06/13 and R08/26f), Else Kröner-Fresenius-Stiftung (P20/07//A11/07), Deutsche Krebshilfe (108,355, 106,142 and 107,239), SBCancer Helmholtz Alliance on Systems Biology and the Global CLL Research Foundation. We thank Antonio Sarno and John Byrd for critical reading of the manuscript. We thank the GCLLSG and the chairman Michael Hallek for long-standing cooperation and support. We thank the European Research Initiative on CLL (ERIC) for ongoing discussions.

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Authors and Affiliations

  1. Department of Internal Medicine III, University of Ulm, Ulm, 89081, Germany

    Thorsten Zenz, Daniel Mertens, Hartmut Döhner & Stephan Stilgenbauer

  2. Cooperation Unit Mechanisms of Leukemogenesis, DKFZ Heidelberg, Germany

    Daniel Mertens

  3. Institute of Cell Biology (Cancer Research), University of Duisburg-Essen Medical School, Essen, Germany

    Ralf Küppers

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Correspondence to Stephan Stilgenbauer.

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The authors receive research funding and other remuneration from Roche, GSK, Bayer Schering pharma and Celgene. They receive other remuneration from Trubion pharmaceuticals.

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DATABASES

National Cancer Institute Drug Dictionary 

alemtuzumab

flavopiridol

fludarabine

lenalidomide

rituximab

OMIM

ataxia–telangiectasia

CLL

FURTHER INFORMATION

Daniel Mertens' laboratory homepage

CLL Global Research Foundation

CLL Research Consortium

CLL Topics

Department of Internal Medicine III at the University of Ulm

European Research Initiative on CLL

The German CLL Study Group

The UK CLL Forum

Glossary

Stereotyped B cell receptors

Strikingly similar B cell receptors, which often arise from the use of common H and L chain V region gene segments that share CDR3 structural features (such as their length, amino acid composition and unique amino acid residues at recombination junctions).

Antigenic drive

CLL cells seem to be selected by a limited set of antigenic epitopes at some point in their development. CLL cells are stimulated by the binding of these antigens to the BCR.

Somatic hypermutation

A process that modifies the immunoglobulin variable region genes by introducing mutations into them at a high rate.

Anergic

A state in which B or T cells are unresponsive and cannot be activated by antigen.

IGHV1-69

A specific IGHV gene found at a high frequency in CLLs with unmutated IGHV.

CpG island

A region of DNA with a high density of cytosine phosphoguanine dinucleotides, which are near the transcriptional start sites of 40% of all mammalian genes. Cytosine methylation in CpG islands is generally associated with stable silencing of the associated gene.

Immunological synapse

The supramolecular structure that is established between a T cell and an antigen-presenting cell or B cell.

Binet stage

A clinical staging system most commonly used in Europe based on lymphadenopathy, spleen and liver size and blood count (red cells and platelets).

Rai classification

A clinical staging system most commonly used in the United States.

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Zenz, T., Mertens, D., Küppers, R. et al. From pathogenesis to treatment of chronic lymphocytic leukaemia. Nat Rev Cancer 10, 37–50 (2010). https://doi.org/10.1038/nrc2764

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