AML1/ETO oncoprotein is directed to AML1 binding regions and co-localizes with AML1 and HEB on its targets

Alessandro Gardini, Matteo Cesaroni, Lucilla Luzi, Akiko J. Okumura, Joseph R. Biggs, Simone P. Minardi, Elisa Venturini, Dong Er Zhang, Pier Giuseppe Pelicci, Myriam Alcalay

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Abstract

A reciprocal translocation involving chromosomes 8 and 21 generates the AML1/ETO oncogenic transcription factor that initiates acute myeloid leukemia by recruiting co-repressor complexes to DNA. AML1/ETO interferes with the function of its wild-type counterpart, AML1, by directly targeting AML1 binding sites. However, transcriptional regulation determined by AML1/ETO probably relies on a more complex network, since the fusion protein has been shown to interact with a number of other transcription factors, in particular E-proteins, and may therefore target other sites on DNA. Genome-wide chromatin immunoprecipitation and expression profiling were exploited to identify AML1/ETO-dependent transcriptional regulation. AML1/ETO was found to co-localize with AML1, demonstrating that the fusion protein follows the binding pattern of the wild-type protein but does not function primarily by displacing it. The DNA binding profile of the E-protein HEB was grossly rearranged upon expression of AML1/ETO, and the fusion protein was found to co-localize with both AML1 and HEB on many of its regulated targets. Furthermore, the level of HEB protein was increased in both primary cells and cell lines expressing AML1/ETO. Our results suggest a major role for the functional interaction of AML1/ETO with AML1 and HEB in transcriptional regulation determined by the fusion protein.

Original languageEnglish
Article numbere1000275
JournalPLoS genetics
Volume4
Issue number11
DOIs
Publication statusPublished - Nov 2008

All Science Journal Classification (ASJC) codes

  • Ecology, Evolution, Behavior and Systematics
  • Molecular Biology
  • Genetics
  • Genetics(clinical)
  • Cancer Research

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    Gardini, A., Cesaroni, M., Luzi, L., Okumura, A. J., Biggs, J. R., Minardi, S. P., Venturini, E., Zhang, D. E., Pelicci, P. G., & Alcalay, M. (2008). AML1/ETO oncoprotein is directed to AML1 binding regions and co-localizes with AML1 and HEB on its targets. PLoS genetics, 4(11), [e1000275]. https://doi.org/10.1371/journal.pgen.1000275