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Blood, 15 November 2008, Vol. 112, No. 10, pp. 4213-4219. Prepublished online as a Blood First Edition Paper on August 15, 2008; DOI 10.1182/blood-2008-05-157255. This Article Full Text (PDF) Supplemental Methods All Versions of this Article: blood-2008-05-157255v1 112/10/4213    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Pallasch, C. P. Articles by Wendtner, C.-M. Search for Related Content PubMed PubMed Citation Articles by Pallasch, C. P. Articles by Wendtner, C.-M. Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted May 15, 2008 Accepted July 25, 2008 Overexpression of TOSO in CLL is triggered by B-cell receptor signaling and associated with progressive disease Christian Philipp Pallasch, Alexandra Schulz, Nadine Kutsch, Janine Schwamb, Susanne Hagist, Hamid Kashkar, Alfred Ultsch, Claudia Wickenhauser, Michael Hallek, and Clemens-Martin Wendtner* Clinic I of Internal Medicine, University of Cologne, Cologne Institute for Medical Microbiology and Immunology, University of Cologne, Cologne Department of Mathematics and Computer Science, Philipps-University Marburg, Marburg Department of Pathology, University of Cologne, Cologne * Corresponding author; email: clemens.wendtner{at}uni-koeln.de. Resistance towards apoptotic stimuli mediated by overexpression of antiapoptotic factors or extracellular survival signals like B-cell receptor stimulation (BCR) are considered to be responsible for accumulation of malignant B cells in CLL. TOSO was identified as overexpressed candidate gene in CLL applying unit-transformation assays of publicly available microarray datasets. Based on CLL samples from 106 patients, TOSO was identified to exhibit elevated relative expression of 6.8 compared to healthy donor B cells using quantitative real-time PCR (p=0.004). High levels of TOSO expression in CLL correlated with high leukocyte count, advanced Binet stage, previous need for chemotherapy and unmutated IgVH status. CD38+ CLL subsets harboring proliferative activity showed enhanced TOSO expression. We evaluated functional mechanisms of aberrant TOSO expression in CLL cells and identified TOSO expression significantly being induced by BCR stimulation compared to control cells (relative expression (RE) 8.25 vs. 4.86, p=0.01). In contrast, CD40L signaling significantly reduced TOSO expression (RE 2.60; p=0.01). In summary, we show that the anti-apoptotic factor TOSO is associated with progressive disease and enhanced in the proliferative CD38+ CLL subset. Both association with unmutated IgVH and the specific induction of TOSO via the BCR suggest autoreactive BCR signaling as a key mediator of apoptosis resistance in CLL. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: H. Kubagawa, S. Oka, Y. Kubagawa, I. Torii, E. Takayama, D.-W. Kang, G. L. Gartland, L. F. Bertoli, H. Mori, H. Takatsu, et al. Identity of the elusive IgM Fc receptor (Fc{micro}R) in humans J. Exp. Med., November 23, 2009; 206(12): 2779 - 2793. [Abstract] [Full Text] [PDF]

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