Abstract
Deletions of the long arm of chromosome 5 occur either as the sole karyotype abnormality in MDS and AML or as part of a complex aberrant karyotype. It was the aim of this study to analyze the impact of the 5q deletion on the expression levels of genes located on chromosome 5q in AML and MDS. Therefore, gene expression analysis was performed in 344 AML and MDS cases using Affymetrix U133A+B oligonucleotide microarrays. The following subgroups were analyzed: AML with sole 5q deletion (n=7), AML with complex aberrant karyotype (n=83), MDS with sole 5q deletion (n=9), and MDS with complex aberrant karyotype (n=9). These were compared to 200 AML and 36 MDS with normal karyotype. In total, 1313 probe sets representing 603 genes cover sequences located on the long arm of chromosome 5. Overall a significant lower mean expression of all genes located on the long arm of chromosome 5 was observed in subgroups with 5q deletion in comparison to their respective control groups (for all comparisons, p<0.05). 36 genes showed a significantly lower expression in all comparisons. These genes are involved in a variety of different biological processes such as signal transduction (CSNK1A1, DAMS), cell cycle regulation (HDAC3, PFDN1) and regulation of transcription (CNOT8). In addition we performed class prediction using support vector machines (SVM). In one approach all 6 different subgroups were analyzed as one class each. While AML and MDS with normal karyotype as well as AML with complex aberrant karyotype were correctly predicted with high accuracies (97%, 81%, and 92%, respectively) AML and MDS with 5q- sole and MDS with complex aberrant karyotype were frequently misclassified as AML with complex aberrant karyotype. In a second approach only two classes were defined: all cases with 5q deletion combined vs. all cases without 5q deletion. 102 out of 108 cases (94%) with 5q deletion were identified correctly supporting the fact that a distinct gene expression pattern is associated with 5q deletion in general. Performing SVM only with genes located on the long arm of chromosome 5 also resulted in a correct prediction of 92 of 108 (85%) stressing the importance of the expression of genes located on chromosome 5 for these AML and MDS subtypes. The top 100 differentially expressed probe sets between cases with and without 5q deletion represented 74 different annotated genes of which 23 are located on the long arm of chromosome 5. They are involved in a variety of different biological functions such as DNA repair (POLE, RAD21, RAD23B), regulation of transcription (ZNF75A, AF020591, MLLT3, HOXB6), protein biosynthesis (UPF2, TINP1, RPL12, RPL14, RPL15) cell cycle control (GMNN, CSPG6, PFDN1) and signal transduction (HINT1, STK24, APP, CAMLG). 10 of the top 74 genes associated with 5q deletion were involved in the CMYC-pathway with upregulation of RAD21, RAD23B, GMMN, CSPG6, APP, POLE STK24 and STAG2, and downregulation of ACTA2, and RPL12. Ten other genes out of the 74 top differentially expressed genes were involved in the TP53 pathway with upregulation of H1F0, PTPN11 and TAF2 and downregulation of DF, UBE2D2, EEF1A1, IGBP1, PPP2CA, EIF2S3, and NACA. In conclusion, loss of parts of the long arm of chromosome 5 leads to a lower expression of genes located on the long arm of chromosome 5. A specific pattern of functionally related genes was identified which shows a lower expression in AML and MDS subtypes with 5q deletion.
Distinct classes of mitotic cyclins are differentially expressed in the soybean shoot apex during the cell cycle.