Array CGH of fusion gene-positive leukemia-derived cell lines reveals cryptic regions of genomic gain and loss.
Human leukemia-derived cell lines containing characteristic chromosomal translocations and inversions have been instrumental in identifying fusion genes implicated in the pathogenesis of the corresponding leukemia. Although chimeric fusion genes usually provide early and essential steps in the development of leukemia, they are not in themselves sufficient, requiring additional genetic events. The nature of these secondary, cooperating genetic events is not known. The advent of genome wide microarray-based methods for assessing copy number changes made it possible to search for cytogenetically invisible regions of chromosome imbalance. We used BAC microarrays with a resolution of 1 Mb to determine whether cryptic regions of deletion or gain were associated with specific leukemia-associated fusion genes in a series of cell lines. To complement the array analysis, we also applied 24-color karyotyping by M-FISH. This revealed cryptic chromosomal translocations and regions of loss or gain in all the cell lines studied. The chromosomal origin of previously unidentified marker chromosomes was revealed. In all cases, chromosomes described as monosomic were shown to be involved in unbalanced translocations with concurrent loss and/or gain of chromosomal material. The extent of these amplified and deleted regions was more accurately defined. Finally, small regions of deletion and amplification, often including genes known to be involved in leukemia progression (for example MYC, TP53, CDKN2A, and KIT), were identified.
Horsley
Sharon W
SW
Section of Haemato-Oncology, Institute of Cancer Research, London, United Kingdom.
Mackay
Alan
A
Iravani
Marjan
M
Fenwick
Kerry
K
Valgeirsson
Haukur
H
Dexter
Tim
T
Ashworth
Alan
A
Kearney
Lyndal
L
D045744:Cell Line, Tumor; D002869:Chromosome Aberrations; D002872:Chromosome Deletion; D050939:Gene Fusion; D023281:Genomics / Q000379:methods; D006801:Humans; D007621:Karyotyping; D007938:Leukemia / Q000235:genetics* / Q000378:metabolism; D008957:Models, Genetic; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods*; D014178:Translocation, Genetic