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Williams–Beuren syndrome critical region-5/non-T-cell activation linker: a novel target gene of AML1/ETO

Oncogene volume 23, pages 9070–9081 (2004)Cite this article

Abstract

The chromosomal translocation t(8;21) fuses the AML1 (RUNX1) gene on chromosome 21 and the ETO gene on chromosome 8 in human acute myeloid leukemias (AMLs), resulting in expression of the chimeric transcription factor AML1/ETO. AML1/ETO-mediated dysregulation of target genes critical for hematopoietic differentiation and proliferation is thought to contribute to the leukemic phenotype. Several mechanisms, including recruitment of histone deacetylases (HDACs) to AML1 target genes, may be responsible for altered gene expression. We used an ecdysone-inducible expression system in the human monoblastic U-937 cell line to isolate genes that were differentially expressed upon induction of AML1/ETO expression. By representational difference analysis (cDNA-RDA), we identified 26 genes whose expression levels were significantly modulated following AML1/ETO induction for 48 h. None of these genes has previously been described as a target of AML1, ETO or AML1/ETO. One gene downregulated by AML1/ETO in vitro, Williams Beuren syndrome critical region 5 (WBSCR5), was expressed in primary t(8;21)-negative AML blasts but not in primary t(8;21)-positive AML blasts, strongly implying a role of this gene in the phenotype of t(8;21)-positive AML. Four upregulated and four downregulated genes were further studied with all-trans-retinoic acid (ATRA), an inducer of differentiation of U-937 cells, and Trichostatin A (TSA), an HDAC inhibitor. Three out of eight genes including WBSCR5 were regulated during ATRA-induced monocytic differentiation of U-937 cells, however, none of them antagonistically, upon both ATRA treatment and AML1/ETO induction. AML1/ETO-associated dysregulation of gene expression was not mediated by a TSA-sensitive mechanism. The identified genes provide a useful model to study the mechanism by which the AML1/ETO fusion protein exerts its function in transcriptional dysregulation in AML. The possible role of WBSCR5 in normal and malignant hematopoiesis warrants further study.

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Acknowledgements

We thank Dr Marie Follo and Klaus Geiger for their excellent support with automated sequencing, Dr Jan Burger for FACS analyses, Dr Florian Otto for many helpful discussions, Dr David G Schatz for valuable suggestions, Dr MA van Dijk for the modified RDA protocol, Prof. Torsten Haferlach for sharing unpublished results and Mahmoud Abdelkarim for technical assistance. Prof. R Pankau and Prof. C Niemeyer provided valuable insight and discussion on WBS. This work was supported by the Deutsche Jose Carreras Leukämie Stiftung, R00/14 and the Deutsche Forschungsgemeinschaft (SFB 364 and Lu 429.5-1).

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  1. Manfred Fliegauf

    Present address: Department of Pediatrics and Adolescent Medicine, University of Freiburg Medical Center, D-79106, Freiburg, Germany

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  1. Division of Hematology/Oncology, University of Freiburg Medical Center, Hugstetter Str. 55, Freiburg, D-79106, Germany

    Manfred Fliegauf, Michael Stock, Tobias Berg & Michael Lübbert

  2. Department of Biology III, Albert-Ludwigs University Freiburg, Freiburg, D-79104, Germany

    Manfred Fliegauf

  3. Department of Biology I, Albert-Ludwigs University Freiburg, Freiburg, D-79104, Germany

    Michael Stock

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Correspondence to Michael Lübbert.

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Fliegauf, M., Stock, M., Berg, T. et al. Williams–Beuren syndrome critical region-5/non-T-cell activation linker: a novel target gene of AML1/ETO. Oncogene 23, 9070–9081 (2004). https://doi.org/10.1038/sj.onc.1208042

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