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

Serena Racanicchi, Chiara Maccherani, Concetta Liberatore, Monia Billi, Vania Gelmetti, Maddalena Panigada, Giovanni Rizzo, Clara Nervi, Francesco Grignani

Research output: Contribution to journalArticle

Abstract

The AML1/ETO and PML/RARα 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/RARα 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/RARα-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.

Original languageEnglish
Pages (from-to)1232-1242
Number of pages11
JournalEMBO Journal
Volume24
Issue number6
DOIs
Publication statusPublished - Mar 23 2005

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Keywords

  • Corepressors
  • Fusion proteins
  • Histone deacetylase
  • Leukemia
  • Retinoic acid

ASJC Scopus subject areas

  • Genetics
  • Cell Biology

Cite this

Racanicchi, S., Maccherani, C., Liberatore, C., Billi, M., Gelmetti, V., Panigada, M., Rizzo, G., Nervi, C., & Grignani, F. (2005). Targeting fusion protein/corepressor contact restores differentiation response in leukemia cells. EMBO Journal, 24(6), 1232-1242. https://doi.org/10.1038/sj.emboj.7600593