title: Overexpression of TOSO in CLL is triggered by B-cell receptor signaling and associated with progressive disease.
abstract: 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.
authors: Laboratory of Cellular Immunotherapy, Clinic I of Internal Medicine, University of Cologne, Cologne, Germany.
authors: Christian Philipp
authors: CP
authors: Pallasch
authors: Alexandra
authors: A
authors: Schulz
authors: Nadine
authors: N
authors: Kutsch
authors: Janine
authors: J
authors: Schwamb
authors: Susanne
authors: S
authors: Hagist
authors: Hamid
authors: H
authors: Kashkar
authors: Alfred
authors: A
authors: Ultsch
authors: Claudia
authors: C
authors: Wickenhauser
authors: Michael
authors: M
authors: Hallek
authors: Clemens-Martin
authors: CM
authors: Wendtner
mesh_terms: 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
chemical_list: 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