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  • The EMBO Journal (2005) 24, 1232 - 1242
  • doi:10.1038/sj.emboj.7600593

Published online: 24 February 2005

Targeting fusion protein/corepressor contact restores differentiation response in leukemia cells

Serena Racanicchi1, Chiara Maccherani1, Concetta Liberatore1, Monia Billi1, Vania Gelmetti2,3, Maddalena Panigada1, Giovanni Rizzo1, Clara Nervi2,3 and Francesco Grignani1

  1. Patologia Generale and Medicina Interna e Scienze Oncologiche, Dipartimento di Medicina Clinica e Sperimentale, Perugia University, Policlinico Monteluce, Perugia, Italy
  2. Dipartimento di Istologia ed Embriologia Medica, Università di Roma 'La Sapienza', Roma, Italy
  3. Parco Bio-Medico Scientifico San Raffaele di Roma, Roma, Italy

Correspondence to:

Francesco Grignani, Medicina Interna e Scienze Oncologiche, Dipartimento di Medicina Clinica e Sperimentale, Perugia University, Policlinico Monteluce, 06100 Perugia, Italy. Tel.: +39 075 572 6264; Fax: +39 075 578 3444; E-mail: fragrig@unipg.it

Received 30 June 2004; Accepted 1 February 2005

The AML1/ETO and PML/RARalpha leukemia fusion proteins induce acute myeloid leukemia by acting as transcriptional repressors. They interact with corepressors, such as N-CoR and SMRT, that recruit a multiprotein complex containing histone deacetylases on crucial myeloid differentiation genes. This leads to gene repression contributing to generate a differentiation block. We expressed in leukemia cells containing PML/RARalpha and AML1/ETO N-CoR protein fragments derived from fusion protein/corepressor interaction surfaces. This blocks N-CoR/SMRT binding by these fusion proteins, and disrupts the repressor protein complex. In consequence, the expression of genes repressed by these fusion proteins increases and differentiation response to vitamin D3 and retinoic acid is restored in previously resistant cells. The alteration of PML/RARalpha–N-CoR/SMRT connections triggers proteasomal degradation of the fusion protein. The N-CoR fragments are biologically effective also when directly transduced by virtue of a protein transduction domain. Our data indicate that fusion protein activity is permanently required to maintain the leukemia phenotype and show the route to developing a novel therapeutic approach for leukemia, based on its molecular pathogenesis.

  • Keywords:

    • corepressors,
    • fusion proteins,
    • histone deacetylase,
    • leukemia,
    • retinoic acid