Multiple molecular mechanisms contribute to radiation sensitivity in mantle cell lymphoma.
Mantle cell lymphomas (MCL) are characterized by their aggressive behavior and poor response to chemotherapy regimens. We report here evidence of increased in vitro radiation sensitivity in two cell lines that we have generated from two MCL patients (UPN1 and UPN2). However, despite their increased radiation sensitivity, UPN2 cells were totally resistant to apoptotic cell death, whereas UPN1 cells underwent massive apoptosis 6 h after irradiation. The frequency of induced chromosomal abnormalities was higher in UPN1 as compared to UPN2. Distinct mechanisms have been found to contribute to this phenotype: a major telomere shortening (UPN1 and UPN2), deletion of one ATM allele and a point mutation in the remaining allele in UPN2, mutation of p53 gene (UPN1 and UPN2) with absence of functional p53 as revealed by functional yeast assays. After irradiation, Ku70 levels in UPN1 increased and decreased in UPN2, whereas in the same conditions, DNA-PKcs protein levels decreased in UPN1 and remained unchanged in UPN2. Thus, irradiation-induced apoptotic cell death can occur despite the nonfunctional status of p53 (UPN1), suggesting activation of a unique pathway in MCL cells for the induction of this event. Overall, our study demonstrates that MCL cells show increased radiation sensitivity, which can be the result of distinct molecular events. These findings could clinically be exploited to increase the dismal response rates of MCL patients to the current chemotherapy regimens.
M'kacher
R
R
Department of Medicine, UPRES EA 27-10, Villejuif, France.
Bennaceur
A
A
Farace
F
F
Laugé
A
A
Plassa
L F
LF
Wittmer
E
E
Dossou
J
J
Violot
D
D
Deutsch
E
E
Bourhis
J
J
Stoppa-Lyonnet
D
D
Ribrag
V
V
Carde
P
P
Parmentier
C
C
Bernheim
A
A
Turhan
A G
AG
D034961:Antigens, Nuclear / Q000235:genetics / Q000378:metabolism; D017209:Apoptosis / Q000235:genetics / Q000528:radiation effects*; D064007:Ataxia Telangiectasia Mutated Proteins; D002453:Cell Cycle / Q000235:genetics / Q000528:radiation effects; D018797:Cell Cycle Proteins; D002869:Chromosome Aberrations; D004265:DNA Helicases; D004260:DNA Repair / Q000235:genetics; D051747:DNA-Activated Protein Kinase; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D000072200:Ku Autoantigen; D020522:Lymphoma, Mantle-Cell / Q000235:genetics* / Q000276:immunology / Q000473:pathology / Q000532:radiotherapy*; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009687:Nuclear Proteins; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism / Q000528:radiation effects; D011836:Radiation Tolerance / Q000235:genetics*; D011839:Radiation, Ionizing; D019098:Telomerase / Q000235:genetics / Q000378:metabolism; D016615:Telomere / Q000235:genetics; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism / Q000528:radiation effects; D025521:Tumor Suppressor Proteins
D034961:Antigens, Nuclear; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D051747:DNA-Activated Protein Kinase; C497263:PRKDC protein, human; D017346:Protein Serine-Threonine Kinases; D019098:Telomerase; D004265:DNA Helicases; C106893:XRCC5 protein, human; C000606509:Xrcc6 protein, human; D000072200:Ku Autoantigen