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Complementing mutations in core binding factor leukemias: from mouse models to clinical applications

Oncogene volume 27, pages 5759–5773 (2008)Cite this article

Abstract

A great proportion of acute myeloid leukemias (AMLs) display cytogenetic abnormalities including chromosomal aberrations and/or submicroscopic mutations. These abnormalities significantly influence the prognosis of the disease. Hence, a thorough genetic work-up is an essential constituent of standard diagnostic procedures. Core binding factor (CBF) leukemias denote AMLs with chromosomal aberrations disrupting one of the CBF transcription factor genes; the most common examples are translocation t(8;21) and inversion inv(16), which result in the generation of the AML1-ETO and CBFβ-MYH11 fusion proteins, respectively. However, in murine models, these alterations alone do not suffice to generate full-blown leukemia, but rather, complementary events are required. In fact, a substantial proportion of primary CBF leukemias display additional activating mutations, mostly of the receptor tyrosine kinase (RTK) c-KIT. The awareness of the impact and prognostic relevance of these ‘second hits’ is increasing with a wider range of mutations tested in clinical trials. Furthermore, novel agents targeting RTKs are emanating rapidly and entering therapeutic regimens. Here, we present a concise review on complementing mutations in CBF leukemias including pathophysiology, mouse models, and clinical implications.

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Acknowledgements

We are grateful for outstanding support by the comments and remarks of both reviewers of this paper. This study was supported by the Deutsche Forschungsgemeinschaft (DFG), Germany (AM), the La Caixa Stiftung–Deutscher Akademischer Austauschdienst (DAAD), Germany (JD), and the German Jose-Carreras Leukemia Foundation (ML), respectively.

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Authors and Affiliations

  1. Department of Hematology/Oncology, University Medical Center Freiburg, Freiburg, Germany

    A M S Müller, J Duque & M Lübbert

  2. Department of Medicine, Division of Blood and Marrow Transplantation, Stanford University Medical Center, Stanford, CA, USA

    A M S Müller & J A Shizuru

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  1. A M S Müller
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  2. J Duque
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  3. J A Shizuru
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  4. M Lübbert
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Correspondence to M Lübbert.

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Müller, A., Duque, J., Shizuru, J. et al. Complementing mutations in core binding factor leukemias: from mouse models to clinical applications. Oncogene 27, 5759–5773 (2008). https://doi.org/10.1038/onc.2008.196

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  • DOI: https://doi.org/10.1038/onc.2008.196

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