1. Targeting fusion protein/corepressor contact restores differentiation response in leukemia cells.
- Author
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Racanicchi S, Maccherani C, Liberatore C, Billi M, Gelmetti V, Panigada M, Rizzo G, Nervi C, and Grignani F
- Subjects
- Acute Disease, Cell Differentiation drug effects, Cell Line, Tumor, Cholecalciferol pharmacology, Core Binding Factor Alpha 2 Subunit, DNA-Binding Proteins antagonists & inhibitors, Gene Expression Regulation, Neoplastic drug effects, Humans, Neoplasm Proteins genetics, Nuclear Proteins antagonists & inhibitors, Nuclear Receptor Co-Repressor 1, Nuclear Receptor Co-Repressor 2, Oncogene Proteins, Fusion genetics, Peptides genetics, Peptides physiology, Protein Structure, Tertiary genetics, Protein Structure, Tertiary physiology, RUNX1 Translocation Partner 1 Protein, Repressor Proteins antagonists & inhibitors, Transcription Factors genetics, Tretinoin pharmacology, DNA-Binding Proteins metabolism, Leukemia, Myeloid metabolism, Neoplasm Proteins metabolism, Nuclear Proteins metabolism, Oncogene Proteins, Fusion metabolism, Repressor Proteins metabolism, Transcription Factors metabolism
- Abstract
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. more...
- Published
- 2005
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