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Oncogenes, Fusion Genes and Tumor Suppressor Genes

Chromatin modifications induced by the AML1-ETO fusion protein reversibly silence its genomic targets through AML1 and Sp1 binding motifs

Leukemia volume 26, pages 1329–1337 (2012)Cite this article

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Abstract

The AML1-ETO fusion protein, which is present in 10–15% of cases of acute myeloid leukemia, is known to repress myeloid differentiation genes through DNA binding and recruitment of chromatin-modifying proteins and transcription factors in target genes. ChIP-chip analysis of human hematopoietic stem/progenitor cells transduced with the AML1-ETO fusion gene enabled us to identify 1168 AML1-ETO target genes, 103 of which were co-occupied by histone deacetylase 1 (HDAC1) and had lost the hyperacetylation mark at histone H4, and 264 showed a K9 trimethylation at histone H3. Enrichment of genes involved in hematopoietic differentiation and in specific signaling pathways was observed in the presence of these epigenetic modifications associated with an ‘inactive’ chromatin status. Furthermore, AML1-ETO target genes had a significant correlation between the chromatin marks studied and transcriptional silencing. Interestingly, AML1 binding sites were absent on a large number of selected AML1-ETO promoters and an Sp1 binding site was found in over 50% of them. Reversible silencing induced by the fusion protein in the presence of AML1 and/or Sp1 transcription factor binding site was confirmed. Therefore, this study provides a global analysis of AML1-ETO functional chromatin modifications and identifies the important role of Sp1 in the DNA binding pattern of AML1-ETO, suggesting a role for Sp1-targeted therapy in this leukemia subtype.

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Acknowledgements

We are grateful to Bibiana Ferreira and Ana Del Río for helpful discussions and ideas and M Carmen Martin for the technical work support. We thank Thomas O’Boyle for manuscript review. This work was supported by the Spanish Government; Grant number AP2008-00339 (AMD), PI08-0878 and CP06/0004 (SA), PI08-0440 (JCC), NIH Grant CA118319 (JMC) and Fundacion Cientifica de la Asociacion Española Contra el Cancer.

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Authors and Affiliations

  1. Molecular Cytogenetics Group, Human Cancer Genetics programme, Centro Nacional Investigaciones Oncologicas (CNIO), Centro de Investigaciones de Enfermedades Raras (CIBERER), Madrid, Spain

    A Maiques-Diaz, S Rodriguez-Perales, J C Cigudosa & S Alvarez

  2. Division of Experimental Hematology and Cancer Biology, Cancer and Blood Diseases Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA,

    F S Chou, M Wunderlich & J C Mulloy

  3. Bioinformatics Unit, Structural Biology and Biocomputing Programme, Centro Nacional Investigaciones Oncólogicas (CNIO), Madrid, Spain

    G Gómez-López

  4. Chromatin and Disease Group, Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), Barcelona, Spain

    F V Jacinto

  5. Department of Genetics, University of Navarra, Pamplona, Spain

    M J Larrayoz & M J Calasanz

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Author contributions

AMD and SA designed and performed the experiments, analyzed data and prepared the manuscript. FSC, MW and JCM developed all the used HSPC models and provided the expression data. GGL performed bioinformatics analyses. FVJ, SRP, JCC and SA participated on the project design. MJL and MJC provided the primary samples.

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Maiques-Diaz, A., Chou, F., Wunderlich, M. et al. Chromatin modifications induced by the AML1-ETO fusion protein reversibly silence its genomic targets through AML1 and Sp1 binding motifs. Leukemia 26, 1329–1337 (2012). https://doi.org/10.1038/leu.2011.376

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