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| Item Type: | Article |
|---|---|
| Title: | Haploinsufficiency of ETV6 and CDKN1B in patients with acute myeloid leukemia and complex karyotype |
| Creators Name: | Feurstein, S. and Rücker, F.G. and Bullinger, L. and Hofmann, W. and Manukjan, G. and Göhring, G. and Lehmann, U. and Heuser, M. and Ganser, A. and Döhner, K. and Schlegelberger, B. and Steinemann, D. |
| Abstract: | BACKGROUND: Acute myeloid leukemia with complex karyotype (CK-AML) is a distinct biological entity associated with a very poor outcome. Since complex karyotypes frequently contain deletions of the chromosomal region 12p13 encompassing the tumor suppressor genes ETV6 and CDKN1B, we aimed to unravel their modes of inactivation in CK-AML. RESULTS: To decipher deletions, mutations and methylation of ETV6 and CDKN1B, arrayCGH, SNP arrays, direct sequencing of all coding exons and pyrosequencing of the 5′UTR CpG islands of ETV6 and CDKN1B were performed. In total, 39 of 79 patients (49%) showed monoallelic deletions of 12p13 according to karyotypic data and 20 of 43 patients (47%) according to genomic profiling. Genomic profiling led to the minimal deleted region covering the 3′-UTR of ETV6 and CDKN1B. Direct sequencing revealed one novel monoallelic frameshift mutation in ETV6 while no mutations in CDKN1B were identified. Furthermore, methylation levels of ETV6 and CDKN1B did not indicate transcriptional silencing of any of these genes. ETV6 and CDKN1B had reduced expression levels in CK-AML patients with deletion in 12p13 as compared to CK-AML without deletion in 12p13, while the other genes (BCL2L14, LRP6, DUSP16 and GPRC5D) located within the minimal deleted region in 12p13 had very low or missing expression in CK-AML irrespective of their copy number status. CONCLUSIONS: ETV6 and CDKN1B are mainly affected by small monoallelic deletions, whereas mutations and hypermethylation play a minor role in CK-AML. Reduced gene dosage led to reduced gene expression levels, pointing to haploinsufficiency as the relevant mechanism of inactivation of ETV6 and CDKN1B in CK-AML. |
| Keywords: | Acute myeloid leukemia (AML), Complex Karyotype, Haploinsufficiency, ETV6, CDKN1B, ArrayCGH, Methylation, Gene Expression |
| Source: | BMC Genomics |
| ISSN: | 1471-2164 |
| Publisher: | BioMed Central |
| Volume: | 15 |
| Page Range: | 784 |
| Date: | 11 September 2014 |
| Additional Information: | Copyright © Feurstein et al.; licensee BioMed Central Ltd. 2014 This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit https://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (https://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. |
| Official Publication: | https://doi.org/10.1186/1471-2164-15-784 |
| PubMed: | View item in PubMed |
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