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A Study on Acute Myeloid Leukemias with Trisomy 8, 11, Or 13, Monosomy 7, Or Deletion 5Q

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A Study on Acute Myeloid Leukemias with Trisomy 8, 11, Or 13, Monosomy 7, Or Deletion 5Q Leukemia (2005) 19, 1224–1228 & 2005 Nature Publishing Group All rights reserved 0887-6924/05 $30.00 www.nature.com/leu Genomic gains and losses influence expression levels of genes located within the affected regions: a study on acute myeloid leukemias with trisomy 8, 11, or 13, monosomy 7, or deletion 5q C Schoch1, A Kohlmann1, M Dugas1, W Kern1, W Hiddemann1, S Schnittger1 and T Haferlach1 1Laboratory for Leukemia Diagnostics, Department of Internal Medicine III, University Hospital Grosshadern, Ludwig-Maximilians-University, Munich, Germany We performed microarray analyses in AML with trisomies 8 aim of this study to investigate whether gains and losses on the (n ¼ 12), 11 (n ¼ 7), 13 (n ¼ 7), monosomy 7 (n ¼ 9), and deletion genomic level translate into altered genes expression also in 5q (n ¼ 7) as sole changes to investigate whether genomic gains and losses translate into altered expression levels of other areas of the genome in AML. genes located in the affected chromosomal regions. Controls were 104 AML with normal karyotype. In subgroups with trisomy, the median expression of genes located on gained Materials and methods chromosomes was higher, while in AML with monosomy 7 and deletion 5q the median expression of genes located in deleted Samples regions was lower. The 50 most differentially expressed genes, as compared to all other subtypes, were equally distributed Bone marrow samples of AML patients at diagnosis were over the genome in AML subgroups with trisomies. In contrast, 30 and 86% of the most differentially expressed genes analyzed: 12 cases with trisomy 8 (AML-TRI8), seven with characteristic for AML with 5q deletion and monosomy 7 are trisomy 11 (AML-TRI11), seven with trisomy 13 (AML-TRI13), located on chromosomes 5 or 7. In conclusion, gain of whole and nine cases with monosomy 7 (AML-MO7), and seven cases chromosomes leads to overexpression of genes located on the with a deletion of the long arm of chromosome 5 (5q) (AML- respective chromosomes. Losses of larger regions of the DEL5q), as well as 104 AML with normal karyotype (AML-NK). genome translate into lower expression of the majority of All karyotype abnormalities were the sole aberrations. All cases genes represented by only one allele. The reduced expression of these genes is the most characteristic difference in gene were analyzed by cytomorphology, chromosome-banding expression profiles between AML with monosomy 7 and AML analysis and fluorescence in situ hybridization (FISH) on with deletion 5q, respectively, and other AML subtypes. There- interphase nuclei using loci-specific probes for EGR1 (5q31), fore, these data provide evidence that gene dosage effects gene RB (13q14), the centromeric regions of chromosomes 7, 8, and expression in AML with unbalanced karyotype abnormalities. 11.3 The proportion of cells carrying the genetic abnormality Losses of specific regions of the genome determine the gene was above 60% in all cases as determined by FISH analyses. The expression profile more strongly than the gain of whole chromosomes. studies abide by the rules of the local Internal Review Board and Leukemia (2005) 19, 1224–1228. doi:10.1038/sj.leu.2403810 the tenets of the revised Helsinki protocol. Published online 19 May 2005 Keywords: acute myeloid leukemia; gene expression; gene dosage Gene expression and statistical analysis We performed gene expression analysis using oligonucleotide Introduction microarrays covering 33 000 transcripts (Affymetrix U133 set) according to the protocol of the manufacturer applying quality Acute myeloid leukemia (AML) is a heterogeneous group of controls as described elsewhere.4,5 For further analysis, only diseases. From a genetic point of view, three subgroups can be probe sets with a known chromosomal localization (www.affy distinguished: (1) AML with normal karyotype, (2) AML with a metrix.com/analysis/) and those expressed at least in one sample primary balanced chromosome aberration, and (3) AML with were used. All probe sets used in this study together with the unbalanced karyotype abnormalities characterized by gains gene they represent and their chromosomal localization are and/or losses of usually larger regions of the genome and no 1 shown in Tables S1a–S1e of the Supplementary Information. For known primary balanced abnormality. The important pathoge- each probe set, the mean expression value was calculated for netic role of leukemia-specific fusion transcripts such as PML- each AML subgroup. Then for each probe set, a ratio ‘mean RARA, AML1-ETO, and CBFB-MYH11 has been proven. The expression level AML unbalanced/mean expression level AML role of genomic gains and losses in AML is less clear. It has been normal’ was determined. In addition, differentially expressed assumed that gene dosage effects may play a role in the genes were identified by means of the two-sample t-statistic pathogenesis of this AML subgroup. Virtaneva et al supported score with correction for unequal variances.6 The analysis was this hypothesis showing that AML with trisomy 8 as the sole programmed using R (version 1.7.1; www.r-project.org/). karyotype abnormality overexpressed genes located on chromo- some 8 compared to AML with normal karyotype.2 It was the Results and discussion Correspondence: Dr C Schoch, Laboratory for Leukemia Diagnostics, Department of Internal Medicine III, University Hospital Grosshadern, Gene copy number abnormalities are characteristic for malig- Ludwig-Maximilians-University of Munich, Marchioninistr. 15, nant diseases and are also found in association with develop- Munich 81377, Germany; Fax: þ 49 89 7095 4971; E-mail: [email protected] mental abnormalities and/or mental retardation. It is reasonable Received 30 November 2004; accepted 12 April 2005; Published to propose that the transcription of genes mapping to online 19 May 2005 chromosomal regions gained or deleted is altered due to a Gene dosage effects in AML C Schoch et al 1225 dosage effect. Differences in the transcriptional regulation of However, DEFA1 was not confirmed (ratio: 0.74). In our series genes may explain why a change in copy number does not the 3 genes most significantly upregulated in AML-TRI8 were: always result in a higher or lower expression of the affected PTK2B, CNOT7, and LYPLA1. PTK2B was identified also by gene. It was the aim of this study to determine the effect of gene Virtaneva et al as upregulated in AML-TRI8 in a comparison of dosage in AML with trisomies 8, 11, 13, monosomy 7, or AML-TRI8 vs AML-NK vs CD34 þ normal stem cells, while the deletion 5q as a sole abnormality. other two genes were not mentioned. Trisomy 11 and 13 Trisomy 8 In all, 1263 of 1693 and 440 of 530 probe sets covering A total of 1052 probe sets cover sequences localized on sequences localized on chromosomes 11 and 13, respectively, chromosome 8 (Table S1a, supplemental material). In all, 835 of were expressed in at least one sample (Table S1b and S1c, them were expressed in at least one sample and were thus used Supplementary Information). The mean expression of 828 out of for further analyses. The mean expression level of 607 of these 1263 (65.6%) probe sets was higher in cases with trisomy 11, 835 (72.6%) probe sets was higher in cases with trisomy 8 as and of 275 out of 440 (62.5%) higher in cases with trisomy 13 as compared to AML with normal karyotype (Figure 1a). The compared to AML with normal karyotype, respectively median expression level of probe sets on chromosome 8 was (Figure 1b). The median expression of probe sets on chromo- 1.27-fold higher in AML-TRI8 cases than in AML-NK (Figure 2a some 11 was 1.25-fold higher in AML-TRI11 cases than in AML- and b) confirming a gene dosage effect as described by NK and the expression of probe sets on chromosome 13 was 2 Virtaneva et al. In that series, seven out of 29 genes most 1.14-fold higher in AML-TRI13 cases than in AML-NK, significantly upregulated in AML-TRI8 for which a chromosomal demonstrating a gene dosage effect also in AML with trisomy assignment could be made, map to chromosome 8: FABP5, 11 and 13 (Figure 2b). PTDSS1, LY6E, COX6C, LYN, SIAHBP1, and DEFA1.In contrast, none of the 25 genes upregulated in AML-NK map to chromosome 8. The following genes identified by Virtaneva et al Monosomy 7 as up-regulated in AML-TRI8 were confirmed in our series: FABP5 (ratio: 1.73), PTDSS1 (ratio: 1.65), LY6E (ratio: 2.0), A total of 1441 probe sets cover sequences localized on COX6C (ratio: 1.34), LYN (ratio: 1.4), and SIAHBP1 (ratio: 1.37). chromosome 7 (Table S1d, Supplementary Information). In all, a Trisomy 8 b Trisomy 11 50% 50% 100 100 10 10 1 1 ratio ratio 0.1 66% 73% 0.1 0.01 0.01 0.001 835 probe sets on chr. 8 1263 probe sets on chr. 11 c Monosomy 7 d Deletion 5q 50% 50% 100 100 10 10 1 1 ratio ratio 0.1 0.1 87% 67% 0.01 0.01 0.001 0.001 1088 probe sets on chr. 7 502 probe sets in 5q13q31 Figure 1 Ratios of mean expression of probe sets affected by change of gene dosage between the respective subtype with gain or loss of one chromosome/chromosomal region in comparison to AML with normal karyotype. (a) In all, 73% of the 835 probe sets located on chromosome 8 show a higher mean expression (ratio41) in cases with trisomy 8 than in AML with normal karyotype. (b) In all, 65% of the 1263 probe sets located on chromosome 11 show a higher mean expression (ratio41) in cases with trisomy 11 than in AML with normal karyotype.
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