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

Resistance toward apoptotic stimuli mediated by overexpression of antiapoptotic factors or extracellular survival signals is considered to be responsible for accumulation of malignant B cells in chronic lymphocytic leukemia (CLL). TOSO was identified as overexpressed candidate gene in CLL, applying...

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Bibliographic Details
Published in:Blood 2008-11, Vol.112 (10), p.4213-4219
Main Authors: Pallasch, Christian Philipp, Schulz, Alexandra, Kutsch, Nadine, Schwamb, Janine, Hagist, Susanne, Kashkar, Hamid, Ultsch, Alfred, Wickenhauser, Claudia, Hallek, Michael, Wendtner, Clemens-Martin
Format: Article
Language:English
Subjects:
ADP-ribosyl Cyclase 1 - metabolism
Apoptosis
Apoptosis Regulatory Proteins - biosynthesis
B-Lymphocytes - metabolism
B-Lymphocytes - pathology
Biological and medical sciences
Disease Progression
Female
Gene Expression Regulation, Leukemic
Hematologic and hematopoietic diseases
Humans
Immunoglobulin Heavy Chains - metabolism
Immunoglobulin Variable Region - metabolism
Leukemia, Lymphocytic, Chronic, B-Cell - metabolism
Leukemia, Lymphocytic, Chronic, B-Cell - pathology
Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis
Male
Medical sciences
Membrane Glycoproteins - metabolism
Membrane Proteins - biosynthesis
Neoplasm Proteins - biosynthesis
Receptors, Antigen, B-Cell - metabolism
Reverse Transcriptase Polymerase Chain Reaction
Signal Transduction
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Summary:Resistance toward apoptotic stimuli mediated by overexpression of antiapoptotic factors or extracellular survival signals is considered to be responsible for accumulation of malignant B cells in chronic lymphocytic leukemia (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 (RE) of 6.8 compared with healthy donor B cells using quantitative real-time polymerase chain reaction (PCR; P = .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 and identified TOSO expression significantly induced by B-cell receptor (BCR) stimulation compared with control cells (RE; 8.25 vs 4.86; P = .01). In contrast, CD40L signaling significantly reduced TOSO expression (RE, 2.60; P = .01). In summary, we show that the antiapoptotic 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.
ISSN:0006-4971
1528-0020
DOI:10.1182/blood-2008-05-157255