Abstract
Approximately 10 to 15 % of acute myeloid leukemia (AML) cases exhibit complex karyotypes, i.e., three or more chromosome abnormalities without presence of a specific fusion transcript. To identify novel genomic regions of interest in AML with complex karyotypes we applied comparative genomic hybridization to microarrays (matrix-CGH) allowing high-resolution genome-wide screening of genomic imbalances. We designed a microarray consisting of 2799 different BAC- or PAC-vectors. A set of 1500 of these clones covers the whole human genome with a physical distance of approximately 1.5 Mb. The remaining 1299 clones either contiguously span genomic regions known to be frequently involved in hematologic malignancies (e.g., 1p, 2p, 3q, 7q, 9p, 11q, 12q, 13q, 17p, 18q) (n=600) or contain oncogenes or tumor suppressor genes (n=699).
Using this microarray platform, 83 AML cases with complex karyotypes were analyzed. Genomic losses were found more frequently than gains; the most frequent losses were deletions of 5q (71%), 17p (53%), 7q (48%); followed by deletions of 18q (30%), 16q (28%), 3p and 12q (20% each), 12p (18%), 20q (17%), and 11q (12%). The most frequent genomic gains were trisomies of 11q (39%) and 8q (31%); followed by trisomies of 1p (22%), 21q (20%), 9p (14%), 22q (13%), 13q (12%), and 6p (10%). In part, some critical segments were delineated to genomic fragments of 0.8 to a few megabase pairs in size. In lost/gained regions parallel analysis of gene expression using microarray technology detected a gene dosage effect with significant lower/higher average gene expression levels across the genes located in the respective regions. Furthermore, 47 high-level DNA amplifications in 19 different regions were identified; amplifications occurring in at least two cases mapped to (candidate genes in the amplicon) 11q23.3-q24.1 (n=10; ETS, FLI1); 11q23.3 (n=8; MLL, DDX6); 21q22 (n=5; ERG, ETS2); 13q12 (n=3; CDX2, FLT1, FLT3, PAN3); 8q24 (n=3; C8FW, MYC); 9p24 (n=2; JAK2); 12p13 (n=2; FGF6, CCND2); and 20q11 (n=2; ID1, BCL2L1). Parallel analysis displayed overexpressed candidate genes in critical amplified region, e.g., C8FW and MYC in 8q24.
In conclusion, using high-resolution genome-wide screening tools such as matrix-CGH allows to unravel the enormous genetic diversity of AML cases with complex karyotypes, and correlation with global gene expression studies facilitates the delineation of disease-related candidate genes located in the critical regions.
Integrated genome-wide genotyping and gene expression profiling reveals BCL11B as a putative oncogene in acute myeloid leukemia with 14q32 aberrations
