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  • Original Paper
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Somatic heterozygous mutations in ETV6 (TEL) and frequent absence of ETV6 protein in acute myeloid leukemia

Abstract

ETV6 (ets translocation variant gene 6) TEL (translocation ets leukemia), encoding a transcriptional repressor, is involved in various translocations associated with human malignancies. Strikingly, the nonrearranged ETV6 allele is often deleted or inactivated in cells harboring these translocations. Although ETV6 translocations are infrequent in acute myeloid leukemia (AML), mutations or deregulated expression of ETV6 may contribute to leukemogenesis. To investigate the involvement of ETV6 in AML, we analysed 300 newly diagnosed patients for mutations in the coding region of the gene. Furthermore, we studied protein expression in 77 patients using two ETV6-specific antibodies. Five somatic heterozygous mutations were detected, which affected either the homodimerization- or the DNA-binding domain of ETV6. The proteins translated from the cDNAs of these mutants were unable to repress transcription and showed dominant-negative effects. In addition, we demonstrate that one-third of AML patients have deficient ETV6 protein expression, which is not related to ETV6 mRNA expression levels. In conclusion, we demonstrate that ETV6 abnormalities are not restricted to translocations and occur more frequently in AML than previously thought. Additional comprehensive studies are required to define the clinical consequence of ETV6 loss of function in AML.

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Acknowledgements

We thank Claudia Erpelinck, Antoinette Beijen for technical assistance, Peter Valk and Roel Verhaak for the ETV6 mRNA expression analysis on the gene array data and Marieke von Lindern for her comments on this paper. We are indebted to Karola van Rooyen for assistance with the preparation of figures. This work was supported by the Dutch Cancer Foundation Koningin Wilhelmina Fonds.

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Correspondence to Ruud Delwel.

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Barjesteh van Waalwijk van Doorn-Khosrovani, S., Spensberger, D., de Knegt, Y. et al. Somatic heterozygous mutations in ETV6 (TEL) and frequent absence of ETV6 protein in acute myeloid leukemia. Oncogene 24, 4129–4137 (2005). https://doi.org/10.1038/sj.onc.1208588

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