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  • Review Article
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Molecular and cellular mechanisms of CLL: novel therapeutic approaches

Nature Reviews Clinical Oncology volume 6, pages 405–418 (2009)Cite this article

Abstract

The mainstay of therapy of chronic lymphocytic leukemia (CLL) is cytotoxic chemotherapy; however, CLL is still an incurable disease with resistance to therapy developing in the majority of patients. In recent years, our understanding of the biological basis of CLL pathogenesis has substantially improved and novel treatment strategies are emerging. Tailoring and individualizing therapy according to the molecular and cellular biology of the disease is on the horizon, and advances with targeted agents such as monoclonal antibodies combined with traditional chemotherapy have lead to improved remission rates. The proposed key role of the B-cell receptor (BCR) in CLL pathogenesis has led to a number of possible opportunities for therapeutic exploitation. We are beginning to understand that the microenviroment is of utmost importance in CLL because certain T-cell subsets and stromal cells support the outgrowth and development of the malignant clone. Furthermore, an increase in our understanding of the deregulated cell-death machinery in CLL is a prerequisite to developing new targeted strategies that might be more effective in engaging with the cell-death machinery. This Review summarizes the progress made in understanding these features of CLL biology and describes novel treatment strategies that have also been exploited in current clinical trials.

Key Points

  • Antigenic input and B-cell receptor (BCR) signaling are important in the pathophysiology of chronic lymphocytic leukemia (CLL)

  • A number of relevant signals downstream of the BCR signal, or that modify its signal, have been implicated in CLL and are currently exploited as targets for therapy

  • The contribution of accessory immune cells and of stromal microenvironment to CLL pathophysiology is starting to be exploited in a therapeutic fashion

  • CLL-specific proapoptotic and antiapoptotic influences contributed by microenvironmental and immunologic cues allow for a unique opportunity to target the core cell-death machinery in various combinations

  • A large number of early clinical trials exploiting such rationales are currently under way and the results will need careful integration into future therapeutic concepts

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Figure 1: The role of BCR signaling in the biology of CLL.
Figure 2: Cellular interactions as potential therapeutic targets in the CLL microenvironment.
Figure 3: Therapeutic roads into the Bcl-2 death-signaling machinery.

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Acknowledgements

We thank Petra Desch for skillful support with graphical presentation. The work of the authors is supported by FWF grants L488-B13, P19481-B12, and SFB 021-P11 and grants of the Province of Salzburg.

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  1. Laboratory for Immunological and Molecular Cancer Research and IIIrd Medical Department with Hematology, Medical Oncology, Hemostaseology, Rheumatology and Infectiology, Paracelsus Medical University Salzburg, Laboratory for Immunological and Molecular Cancer Research, Salzburg, Austria

    Lisa Pleyer, Alexander Egle, Tanja Nicole Hartmann & Richard Greil

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Pleyer, L., Egle, A., Hartmann, T. et al. Molecular and cellular mechanisms of CLL: novel therapeutic approaches. Nat Rev Clin Oncol 6, 405–418 (2009). https://doi.org/10.1038/nrclinonc.2009.72

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