The resistance of B-CLL cells to DNA damage-induced apoptosis defined by DNA microarrays.
B-cell chronic lymphoid leukemia (BCLL) is a highly heterogeneous human malignancy, presumably reflecting specific molecular alterations in gene expression and protein activity that are thought to underlie the variable disease outcome. Most B-CLL cell samples undergo apoptotic death in response to DNA damage. However, a clinically distinct aggressive subset of B-CLL is completely resistant in vitro to irradiation-induced apoptosis. We therefore addressed 2 series of microarray analyses on 4 sensitive and 3 resistant B-CLL cell samples and compared their gene expression patterns before and after apoptotic stimuli. Data analysis pointed out 16 genes whose expression varied at least 2-fold specifically in resistant cells. We validated these selected genes by real-time quantitative reverse transcription-polymerase chain reaction (RT-PCR) on 7 microarray samples and confirmed their altered expression level on 15 additional B-CLL cell samples not included in the microarray analysis. In this manner, in 11 sensitive and 11 resistant B-CLL cell samples tested, 13 genes were found to be specific for all resistant samples: nuclear orphan receptor TR3, major histocompatibility complex (MHC) class II glycoprotein HLA-DQA1, mtmr6, c-myc, c-rel, c-IAP1, mat2A, and fmod were up-regulated, whereas MIP1a/GOS19-1 homolog, stat1, blk, hsp27, and ech1 were down-regulated. In some cases, the expression profile may be dependent on the status of p53. Some of these genes encode general apoptotic factors but also exhibit lymphoid cell specificities that could potentially be linked to the development of lymphoid malignancies (MIP1alpha, blk, TR3, mtmr6). Taken together, our data define new molecular markers specific to resistant B-CLL subsets that might be of clinical relevance.
Vallat
Laurent
L
Direction des Sciences du Vivant-Départment de Radiopathologie et Radiobiologie, Fontenay aux Roses, France.
Magdelénat
Henri
H
Merle-Béral
Helene
H
Masdehors
Peggy
P
Potocki de Montalk
Gabrielle
G
Davi
Frédéric
F
Kruhoffer
Mogens
M
Sabatier
Laure
L
Orntoft
Torben F
TF
Delic
Jozo
J
D017209:Apoptosis / Q000235:genetics / Q000528:radiation effects*; D014408:Biomarkers, Tumor / Q000032:analysis; D004249:DNA Damage / Q000502:physiology* / Q000528:radiation effects; D020869:Gene Expression Profiling / Q000379:methods; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000235:genetics / Q000473:pathology* / Q000532:radiotherapy; D016131:Lymphocyte Subsets; D020411:Oligonucleotide Array Sequence Analysis; D016159:Tumor Suppressor Protein p53 / Q000502:physiology
D014408:Biomarkers, Tumor; D016159:Tumor Suppressor Protein p53