Haploinsufficiency of ETV6 and CDKN1B in patients with acute myeloid leukemia and complex karyotype

BMC Genomics

Doris Steinemann²  Brigitte Schlegelberger²  Konstanze Döhner⁴  Arnold Ganser³  Michael Heuser³  Ulrich Lehmann¹  Gudrun Göhring²  Georgi Manukjan²  Winfried Hofmann²  Lars Bullinger⁴  Frank G Rücker⁴  Simone Feurstein² 

[1] Institute of Pathology, Hannover Medical School, Hannover, Germany;Institute of Cell and Molecular Pathology, Hannover Medical School, Hannover, Germany;Department of Hematology, Hemostasis, Oncology, and Stem Cell Transplantation, Hannover Medical School, Hannover, Germany;Department of Internal Medicine III, University Hospital of Ulm, Ulm, Germany

关键词: Gene expression;    Methylation;    ArrayCGH;    CDKN1B;    ETV6;    Haploinsufficiency;    Complex karyotype;    Acute myeloid leukemia (AML);   

Others  :  1140558
DOI  :  10.1186/1471-2164-15-784

 received in 2014-03-04, accepted in 2014-09-08,  发布年份 2014

【 摘 要 】

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.

【 授权许可】

   
2014 Feurstein et al.; licensee BioMed Central Ltd.

【 图 表 】

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