Further Insights into the Pathogenesis of AML with Complex Aberrant Karyotype by Performing a Combination of Conventional CGH, Gene Expression and Genomic Array Analysis.
Authors: Schoch Claudia , Kohlmann Alexander , Rauhut Sonja , Dicker Frank , Schnittger Susanne , Kern Wolfgang , Haferlach Torsten 
Published: April 2020

Abstract
Acute myeloid leukemia (AML) with complex aberrant karyotype is a distinct biological entity. It is characterized by: 1) a sharp increase of incidence above age 50, 2) a characteristic pattern of chromosomal gains and especially losses, i.e. losses of 5q14q33, 7q32q35, and 17p13 translating into a reduced expression of genes located in these regions, 3) a unique gene expression pattern including an upregulation of genes involved in DNA repair, 4) a high incidence of TP53 deletions and/or mutations and 5) an overall unfavorable prognosis. So far, the pathogenetic role of the lost and gained chromosomal regions in AML with complex aberrant karyotype is unclear. In a first step we tested whether a correlation between genomic imbalances and changes in gene expression exists. Therefore, gene expression analysis was performed in 24 cases of AML with complex aberrant karyotype and in 57 AML with normal karyotype for comparison. Overall, genes located on 5q, which is deleted in the majority of cases, showed a significantly lower expression in AML with complex aberrant karyotype as compared to AML with normal karyotype. Furthermore, for each chromosomal band on chromosome 5 ratios were calculated between AML with complex aberrant karyotype and AML with normal karyotype. Ratios lower than 0.90 were found for all chromosome bands between 5q14 and 5q34 (range 0.64–0.88) with lowest values for 5q15 and 5q22 (0.64 and 0.68). Between 61% and 90% of genes located in one of the chromosome bands 5q14 to 5q34 showed a lower expression in AML with complex aberrant karyotype compared with AML with normal karyotype. An overall reduced expression of genes was also observed in other frequently lost regions such as 7q and 17p, while an overall higher expression of genes located in gained regions such as 1p, 8q and 11q was detected. However, not all genes located within a deleted or gained region showed an altered expression. In order to perform more precise correlations between the copy number of individual genes and their expression 33 cases with AML and complex aberrant karyotype were analyzed in parallel with conventional comparative hybridization, genomic arrays (Affymetrix 10K arrays) and gene expression arrays (Affymetrix U133A+B or 2.0 plus). The lost and gained regions detected in conventional CGH were confirmed by data obtained from the genomic arrays. In addition, gained and lost regions could be mapped more precisely. Interestingly, the genomic arrays revealed that even large deletions are truly continuous, although not all genes from the respective regions showed a lower expression. In contrast at the borders of amplifications amplified genes alternated with non-amplified genes. In conclusion, a detailed analysis on the genomic as well as on the gene expression level might lead to further insights into the pathogenesis of AML with complex aberrant karyotype and may also serve as a new diagnostic tool in the near future.