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Genetics, Gene Expression, and Targeted Therapies in Chronic Lymphocytic Leukemia

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Abstract:

Chronic lymphocytic leukemia (CLL) represents the most common leukemia among adults in the Western countries. CLL is a remarkably diverse disorder following an extremely variable clinical course. Some patients have an indolent disease that may never require treatment. In others a progressive clinical course is rapidly fatal. CLL affects mainly elderly individuals, but about a third of patients are less than 60 years of age at diagnosis. Traditionally, the therapeutic procedures were aimed at palliation, but over the recent years highly effective and potentially curative approaches such as combined antibody-chemotherapy and autologous or allogeneic stem cell transplantation have been developed. In parallel there has been progress in the understanding of pathogenesis and outcome prediction. The cornerstones to estimate prognosis are the clinical staging systems of Rai and Binet. To refine outcome prediction for individual patients there has been intensive work on biological factors of potential prognostic relevance. Among these, the genetic characteristics of the CLL cells that can be divided into genomic aberrations and the mutation status of the variable segments of immunoglobulin- heavy chain genes (VH) have attained considerable importance. In addition, data on gene expression of CLL cells are accumulating which further characterize the CLL subgroups. In this context, the expression of ZAP-70 has been recognized a useful surrogate marker to predict the VH mutation status and outcome of CLL patients. At present, targeted therapies are focused on humanized antibodies that bind proteins expressed on the surface of CLL cells. The most prominent agents of these are the anti-CD52 antibody alemtuzumab and the anti-CD20 antibody rituximab, which are currently being tested in clinical trials. To identify CLL-specific gene expression products as candidates for targeted therapies will be an important part of CLL research in the next years.





Keywords: Genomic aberrations; VH mutation status; ZAP-70; alemtuzumab; antibody; mRNA expression; protein expression; rituximab

Document Type: Research Article

DOI: http://dx.doi.org/10.2174/138945006778559184

Affiliations: Department of Internal Medicine III, University of Ulm, Robert-Koch-Str. 8, 89081 Ulm, Germany.

Publication date: October 1, 2006

More about this publication?
  • Current Drug Targets aims to cover the latest and most outstanding developments on the medicinal chemistry and pharmacology of molecular drug targets e.g. disease specific proteins, receptors, enzymes, genes. Each issue of the journal will be devoted to a single timely topic, with series of in-depth reviews, written by leaders in the field, covering a range of current topics on drug targets. These issues will be organized and led by a guest editor who is a recognized expert in the overall topic. As the discovery, identification, characterisation and validation of novel human drug targets for drug discovery continues to grow; this journal will be essential reading for all pharmaceutical scientists involved in drug discovery and development.
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