Expression of tumour necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) receptors and sensitivity to TRAIL-induced apoptosis in primary B-cell acute lymphoblastic leukaemia cells.
Because tumour necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) (Apo2 ligand) preferentially kills malignant cells while sparing normal cells, it may be therapeutically useful against cancers, including those of haematopoietic origin. Although the activity of TRAIL has been studied in tumour cell lines and in a limited number of different primary tumours, its overall activity in a large number of uniform cases of primary tumours is not known. We therefore studied the activity of TRAIL in 29 primary precursor B-cell acute lymphoblastic leukaemia (ALL) samples. TRAIL was found to have a modest activity as it killed a maximum of 29% of ALL cells within 18 h compared with killing 75% of Jurkat cells. The sensitivity to TRAIL did not correlate with the pattern of TRAIL receptor expression or FLIP expression, as determined by Western blot analysis. The CD40 receptor, which can transduce survival signals in mature malignant B cells, was less frequently expressed on ALL cells, but incubation with an exogenous soluble CD40 ligand trimer did not rescue them from spontaneous apoptosis and did not mediate their resistance to TRAIL. Further, although ALL cells expressed TRAIL protein, they failed to kill target Jurkat cells in a TRAIL-dependent manner. Our data delineate major biological differences between mature and precursor malignant B cells and suggest a limited therapeutic role for TRAIL as a single agent in primary B-cell ALL.
Clodi
K
K
Children's Cancer Research Institute, Vienna, Austria, The University of Texas M.D. Anderson Cancer Center, Houston, TX, USA. clodi@ccri.uniwie.ac.at
Wimmer
D
D
Li
Y
Y
Goodwin
R
R
Jaeger
U
U
Mann
G
G
Gadner
H
H
Younes
A
A
D000293:Adolescent; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins; D015153:Blotting, Western / Q000379:methods; D002051:Burkitt Lymphoma / Q000188:drug therapy / Q000378:metabolism*; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; D023201:CD40 Ligand / Q000378:metabolism; D002352:Carrier Proteins / Q000378:metabolism; D002648:Child; D002675:Child, Preschool; D005260:Female; D058851:GPI-Linked Proteins; D006801:Humans; D007223:Infant; D047908:Intracellular Signaling Peptides and Proteins; D019169:Jurkat Cells; D008024:Ligands; D008297:Male; D008562:Membrane Glycoproteins / Q000627:therapeutic use*; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D018124:Receptors, Tumor Necrosis Factor / Q000378:metabolism*; D053320:Receptors, Tumor Necrosis Factor, Member 10c; D053221:TNF-Related Apoptosis-Inducing Ligand; D014407:Tumor Cells, Cultured / Q000187:drug effects*; D053319:Tumor Necrosis Factor Decoy Receptors; D014409:Tumor Necrosis Factor-alpha / Q000627:therapeutic use*; D019014:fas Receptor
D051017:Apoptosis Regulatory Proteins; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; C506386:CFLAR protein, human; D002352:Carrier Proteins; D058851:GPI-Linked Proteins; D047908:Intracellular Signaling Peptides and Proteins; D008024:Ligands; D008562:Membrane Glycoproteins; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D018124:Receptors, Tumor Necrosis Factor; D053320:Receptors, Tumor Necrosis Factor, Member 10c; D053221:TNF-Related Apoptosis-Inducing Ligand; C105190:TNFRSF10A protein, human; C505639:TNFRSF10B protein, human; C108661:TNFRSF10C protein, human; C505653:TNFSF10 protein, human; D053319:Tumor Necrosis Factor Decoy Receptors; D014409:Tumor Necrosis Factor-alpha; D019014:fas Receptor; D023201:CD40 Ligand