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 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 IgV(H) 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 IgV(H) and the specific induction of TOSO via the BCR suggest autoreactive BCR signaling as a key mediator of apoptosis resistance in CLL.
Pallasch
Christian Philipp
CP
Laboratory of Cellular Immunotherapy, Clinic I of Internal Medicine, University of Cologne, Cologne, Germany.
Schulz
Alexandra
A
Kutsch
Nadine
N
Schwamb
Janine
J
Hagist
Susanne
S
Kashkar
Hamid
H
Ultsch
Alfred
A
Wickenhauser
Claudia
C
Hallek
Michael
M
Wendtner
Clemens-Martin
CM
D051997:ADP-ribosyl Cyclase 1 / Q000378:metabolism; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins / Q000096:biosynthesis*; D001402:B-Lymphocytes / Q000378:metabolism* / Q000473:pathology; D018450:Disease Progression; D005260:Female; D015973:Gene Expression Regulation, Leukemic; D006801:Humans; D007143:Immunoglobulin Heavy Chains / Q000378:metabolism; D007135:Immunoglobulin Variable Region / Q000378:metabolism; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008562:Membrane Glycoproteins / Q000378:metabolism; D008565:Membrane Proteins / Q000096:biosynthesis*; D009363:Neoplasm Proteins / Q000096:biosynthesis*; D011947:Receptors, Antigen, B-Cell / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction
D051017:Apoptosis Regulatory Proteins; C112037:FCMR protein, human; D007143:Immunoglobulin Heavy Chains; D007135:Immunoglobulin Variable Region; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; D009363:Neoplasm Proteins; D011947:Receptors, Antigen, B-Cell; C498154:CD38 protein, human; D051997:ADP-ribosyl Cyclase 1