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Epigenetic Modifications Mediated by the AML1/ETO and MLL Leukemia Fusion Proteins

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Abstract

AML1/ETO and MLL fusion proteins are among the most common chimeric transcription factors created by chromosomal translocations in acute myeloid leukemia (AML) whose pathogenic roles involve perturbations of epigenetic mechanisms of gene regulation. AML1/ETO is caused by the t(8;21) translocation and is present in approximately 12–15 % of AMLs. It acts as an epigenetic modifier by aberrantly recruiting histone deacetylases (HDACs) and DNA methyltransferases (DNMTs) to target promoters and repressing the expression of its subordinate genes. AML1/ETO-induced epigenetic modifications may be reversed by both HDAC and DNMT inhibitors, restoring the expression of inappropriately silenced genes. Diverse MLL fusion proteins are created by a remarkable variety of translocations involving chromosome band 11q23 in approximately 10 % of AMLs. MLL fusion proteins promote constitutive expression of target genes through various mechanisms involving aberrant recruitment of transcriptional elongation factors (P-TEFb, ELL), chromatin-modifying acetyltransferases (CBP, P300), or histone methyltransferases (DOT1L, PRMT1). Selective targeted inhibition of MLL-associated factors that write or read the histone modifications in chromatin of MLL target genes displays promising efficacy in preclinical studies.

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Acknowledgments

We would like to thank Heiko Becker and Leticia Solari for reviewing the manuscript and Norm Cyr for graphic design. J. Duque-Afonso was funded by a grant from LaCaixa-DAAD (ref. 314, A/05/29785), the Fellowship Program of the Department of Hematology/Oncology of the University of Freiburg, and is currently funded by the German Research Foundation (DFG, ref. DU 1287/2-1). M. Lübbert is supported by the DFG (SPP 1463 ref. LU 429/7-1 and CRC 992-C04 LU429/9-1). M. Cleary is supported by grants from the National Cancer Institute and Leukemia and Lymphoma Society. The authors have no conflicting financial interests.

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  1. Department of Hematology/Oncology, University Medical Center Freiburg, University of Freiburg, Hugstetterstr. 55, Freiburg, D-79106, Germany

    Jesús Duque-Afonso MD & Michael Lübbert MD, PhD

  2. Department of Pathology, Stanford University Medical Center, 300 Pasteur Dr., Stanford, CA, 94305-5324, USA

    Jesús Duque-Afonso MD & Michael L. Cleary MD

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

    Michael Lübbert

  2. Norris Comprehensive Cancer Center Urologic Cancer Res. Lab., University of Southern California Dept. Biochemistry & Molecular Biology, Los Angeles, California, USA

    Peter A. Jones

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Duque-Afonso, J., Lübbert, M., Cleary, M.L. (2014). Epigenetic Modifications Mediated by the AML1/ETO and MLL Leukemia Fusion Proteins. In: Lübbert, M., Jones, P. (eds) Epigenetic Therapy of Cancer. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-38404-2_6

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  • Publisher Name: Springer, Berlin, Heidelberg

  • Print ISBN: 978-3-642-38403-5

  • Online ISBN: 978-3-642-38404-2

  • eBook Packages: MedicineMedicine (R0)

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