Identification of chromosomal loci associated with non-P-glycoprotein-mediated multidrug resistance to topoisomerase II inhibitor in lung adenocarcinoma cell line by comparative genomic hybridization
S. Struski et al., Identification of chromosomal loci associated with non-P-glycoprotein-mediated multidrug resistance to topoisomerase II inhibitor in lung adenocarcinoma cell line by comparative genomic hybridization, GENE CHROM, 30(2), 2001, pp. 136-142
In order to identify genomic changes associated with an etoposide resistanc
e acquisition, we used comparative genomic hybridization (CCH) to compare a
human lung adenocarcinoma cell line, A549 wild type, and three sublines, A
549-VP1-3, exposed to increasing concentrations of the topoisomerase II inh
ibitor, VP16. R-banding karyotype, fluorescence in situ hybridization (FISH
), and Southern blot for the MLL gene were also performed. The CGH analysis
showed that the A549-VP3 cell line shared chemoresistance-specific abnorma
lities (amplification of 11q23-qter, loss of chromosome 17, and deletions o
f 2p14-pter and 2q23-q24). FISH analysis confirmed the loss of one chromoso
me 17 in the three resistant sublines and revealed an increased fragmentati
on of chromosome 2 in more than two segments, depending on the etoposide co
ncentration. FISH with an MLL gene probe showed additional signals of MLL (
from three in the A549-WT to seven in the A549-VP3 cell line) translocated
onto several other chromosomes, Southern blot indicated an amplification of
the MLL gene, dependent on the etoposide concentration, without gene rearr
angement. The CGH results are suggestive of loci that could be associated w
ith the acquisition of an etoposide-chemoresistant phenotype. Deletion of t
he 2p region has already been reported, without any candidate gene being id
entified. The role of MLL in leukemogenesis has previously been demonstrate
d, but its role in the development of other tumors or its significance in t
he chemoresistance process remains to be elucidated. (C) 2001 Wiley-Liss, I
nc.