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Identification and characterization of novel AML1-ETO fusion transcripts in pediatric t(8;21) acute myeloid leukemia: a report from the Children's Oncology Group

Oncogene volume 27, pages 4933–4942 (2008)Cite this article

Abstract

t(8;21)(q22;q22) results in the AML1-ETO (A1E) fusion gene and is a common cytogenetic abnormality in acute myeloid leukemia (AML). Although insertions at the breakpoint region of the A1E fusion transcripts have been reported, additional structural alterations are largely uncharacterized. By RT–PCR amplifications and DNA sequencing, numerous in-frame and out-of-frame AML1b-ETO and AML1c-ETO transcripts were identified in 13 pediatric t(8;21) AMLs, likely resulting from alternate splicing, internal deletions and/or breakpoint region insertions involving both the AML1 (RUNX1) and ETO regions. The in-frame A1E fusion transcript forms represented minor forms. These structure alterations were found in AML1c-ETO but not AML1b-ETO transcripts in two adult t(8;21) AMLs. Although no analogous alterations were detected in native AML1b transcripts, identical alterations in native ETO transcripts were identified. When transfected into HeLa cells, only AML1b, and not the in-frame A1E forms, transactivated the GM-CSF promoter. In co-transfection experiments, the effects of A1E proteins on GM-CSF transactivation by AML1b ranged from repressive to activating. Our results demonstrate a remarkable and unprecedented heterogeneity in A1E fusion transcripts in t(8;21) myeloblasts and suggest that synthesis of alternate A1E transcript and protein forms can significantly impact the regulation of AML1 responsive genes.

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Acknowledgements

We thank Dr Robert J Arceci and the Children's Oncology Group AML Biology Subcommittee for authorizing and providing the clinical specimens that made this study possible. This work was supported by grants from the Karmanos Cancer Institute, Leukemia Research Life, the Children's Research Center of Michigan, the Children's Leukemia Foundation of Michigan, the National Cancer Institute (CA92308 and CA76641), the Leukemia and Lymphoma Society, BPCT Golf Charity, the Sehn Family Foundation and the Dale Meyer Memorial Endowment for Leukemia Research. JW Taub is a Scholar in Clinical Research of the Leukemia and Lymphoma Society. This work was also supported by the Pediatric Oncology Group Grant CA30969 and the Children's Oncology Group Grant CA98543.

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Authors and Affiliations

  1. Developmental Therapeutics Program, Barbara Ann Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, MI, USA

    K M LaFiura, H Edwards, J W Taub, L H Matherly, J A Fontana, Y Ravindranath & Y Ge

  2. Division of Pediatric Hematology/Oncology, Children's Hospital of Michigan, Detroit, MI, USA

    J W Taub & Y Ravindranath

  3. Department of Pediatrics, Wayne State University School of Medicine, Detroit, MI, USA

    J W Taub, Y Ravindranath & Y Ge

  4. Department of Pharmacology, Wayne State University School of Medicine, Detroit, MI, USA

    L H Matherly & Y Ge

  5. Department of Medicine, John D Dingell Veterans Affairs Medical Center, Detroit, MI, USA

    J A Fontana

  6. Division of Hematology/Oncology, Department of Pathology, Barbara Ann Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, MI, USA

    A N Mohamed

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  1. K M LaFiura
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  2. H Edwards
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Correspondence to Y Ge.

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Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc).

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LaFiura, K., Edwards, H., Taub, J. et al. Identification and characterization of novel AML1-ETO fusion transcripts in pediatric t(8;21) acute myeloid leukemia: a report from the Children's Oncology Group. Oncogene 27, 4933–4942 (2008). https://doi.org/10.1038/onc.2008.134

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