Increased genomic alteration complexity and telomere shortening in B-CLL cells resistant to radiation-induced apoptosis.
B-cell chronic lymphocytic leukemia (B-CLL) results in an accumulation of mature CD5(+)/CD23(+) B cells due to an uncharacterized defect in apoptotic cell death. B-CLL is not characterized by a unique recurrent genomic alteration but rather by genomic instability giving rise frequently to several chromosomal aberrations. Besides we reported that approximately 15% of B-CLL patients present malignant B-cells resistant to irradiation-induced apoptosis, contrary to approximately 85% of patients and normal human lymphocytes. Telomere length shortening is observed in radioresistant B-CLL cells. Using fluorescence in situ hybridization (FISH) and multicolour FISH, we tested whether specific chromosomal aberrations might be associated with the radioresistance of a subset of B-CLL cells and whether they are correlated with telomere shortening. In a cohort of 30 B-CLL patients, all of the radioresistant B-CLL cell samples exhibited homozygous or heterozygous deletion of 13q14.3 in contrast to 52% of the radiosensitive samples. In addition to the 13q14.3 deletion, ten out of the 11 radioresistant B-cell samples had another clonal genomic alteration such as trisomy 12, deletion 17p13.1, mutation of the p53 gene or translocations in contrast to only three out of 19 radiosensitive samples. Telomere fusions and non-reciprocal translocations, hallmarks of telomere dysfunction, are not increased in radioresistant B-CLL cells. These findings suggest (i) that the 13q14.3 deletion accompanied by another chromosomal aberration is associated with radioresistance of B-CLL cells and (ii) that telomere shortening is not causative of increased clonal chromosomal aberrations in radioresistant B-CLL cells.
Salin
H
H
Laboratoire de Radiobiologie et d'Oncologie, CEA, DSV/iRCM, Fontenay-aux-Roses, France.
Ricoul
M
M
Morat
L
L
Sabatier
L
L
D017209:Apoptosis / Q000528:radiation effects; D001402:B-Lymphocytes / Q000473:pathology; D002869:Chromosome Aberrations; D002882:Chromosomes, Human, Pair 13 / Q000235:genetics / Q000528:radiation effects; D042822:Genomic Instability; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D008677:Metaphase; D017384:Sequence Deletion / Q000528:radiation effects; D019098:Telomerase / Q000378:metabolism; D016615:Telomere / Q000235:genetics* / Q000648:ultrastructure
D019098:Telomerase