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Molecular characterization of genomic AML1-ETO fusions in childhood leukemia

Leukemia volume 15, pages 1906–1913 (2001)Cite this article

Abstract

T(8;21) AML1(CBFA2)-ETO(MTG8) is the most common chromosomal translocation in acute myeloid leukemia (AML) in both children and adults. We sought to understand the structure and gain insight into the fusion process between AML1 and ETO by sequencing genomic fusions in 17 primary childhood AMLs and two cell lines with t(8;21). Reciprocal translocations were sequenced for seven of the 19 samples. We assumed a null hypothesis that the translocation breakpoints would be evenly distributed along the intronic breakpoint cluster regions. Testing for multimodality via smoothed bootstrap statistical methods suggested, however, the presence of two separate cluster regions within both the AML1 and ETO breakpoint cluster regions. ETObreakpoints were predominantly located in intron 1B in a defined cluster 5′ of exon 1A (scan statistic P value = 0.00001). All patients with available RNA expressed an AML1-ETO mRNA fusion between exon 5 of AML1 and exon 2 of ETO. Since the structural restraints for the fusion protein of AML1-ETO exclude exon 1A, we reason that ETO intron 1B harbors a structural feature with propensity for breakage and/or recombination. Chromosomal breakpoints displayed evidence of fusion by a non-homologous end joining process, with microhomologies and nontemplate nucleotides at some fusion junctions. Breakpoints in general displayed similar complexity of duplications, deletions, and insertions to other common pediatric leukemia translocations (TEL-AML1, MLL-AF4, PML-RARA, CBFB-MYH11) that we and others have analyzed.

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Acknowledgements

We thank the UK Childhood Cancer Study Group and individual clinicians in the UK and California for access to patient material. We thank also Susan Colman, Dr Xiaomei Ma, Yunxia Wang, and Dr Luoping Zhang for initial processing and abstracting of samples. We also thank Professors N Kamada and S Matozaki for providing cell lines. These studies were supported by a Leukaemia Research Fund Specialist Programme grant (ZX, MFG), and grants from the National Institutes of Health (PB (ES09137), MTS (ES04705), MRS (AI40906, AI39932), JLW (CA89032)).

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Authors and Affiliations

  1. Leukaemia Research Fund Centre, Institute of Cancer Research, London, UK

    Z Xiao & MF Greaves

  2. Division of Public Health Biology and Epidemiology, University of California, Berkeley, CA, USA

    P Buffler

  3. Division of Environmental Health Sciences, University of California, Berkeley, CA, USA

    MT Smith

  4. Division of Biostatistics, University of California, San Francisco, CA, USA

    MR Segal

  5. Department of Epidemiology and Biostatistics, Laboratory for Molecular Epidemiology, University of California, San Francisco, CA, USA

    BM Dicks, JK Wiencke & JL Wiemels

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  1. Z Xiao
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Xiao, Z., Greaves, M., Buffler, P. et al. Molecular characterization of genomic AML1-ETO fusions in childhood leukemia. Leukemia 15, 1906–1913 (2001). https://doi.org/10.1038/sj.leu.2402318

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