Overexpression of TOSO in CLL is triggered by B-cell receptor signaling and associated with progressive disease

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Blood First Edition Paper, prepublished online August 15, 2008; DOI

10.1182/blood-2008-05-157255.

Overexpression of TOSO in CLL is triggered by B-cell receptor signaling and

associated with progressive disease

Christian Philipp Pallasch, andra Schulz, Nadine Kutsch, Janine Schwamb,

ne Hagist, Hamid Kashkar, Alfred Ultsch, Wickenhauser,

Hallek, and Clemens- 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@... .

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.