Targeting fusion protein/corepressor contact restores differentiation response in leukemia cells
Open accessAbstract
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.
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The ability of PML/RARα to block differentiation of transfected myeloid cells depends on an intact N-CoR-binding region in the RAR moiety of the fusion protein.
“ability of PML/RARα to block differentiation of transfected myeloid cells depends on an intact N-CoR-binding region in the RAR moiety of the fusion protein (Racanicchi et al, 2005).”
From Unlocking the potential of retinoic acid in anticancer therapy (2014) · cites this paper as Racanicchi et al, 2005
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Unlocking the potential of retinoic acid in anticancer therapy
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- Authors
- Racanicchi, S., Maccherani, C., Liberatore, C., Billi, M., Gelmetti, V., Panigada, M., Rizzo, G., Nervi, C., & Grignani, F.
- Affiliations
- University of Perugia (IT)
- Sapienza University of Rome (IT)
- Corresponding author
- Grignani, Francesco
- Venue
- The EMBO Journal
- Published
- 2005-02-24
- Volume
- 24
- Issue
- 6
- Pages
- 1232-1242
- ISSN
- 0261-4189 (ISSN-L)
- 1460-2075
- PMC
- PMC556397
- OpenAlex
- W2007657789
- Cited by
- 36
- References
- 60
- Citations by year
- 2022: 1 · 2020: 2 · 2019: 1 · 2015: 2 · 2014: 2 · 2013: 2 · 2012: 2
- FWCI
- 1.88
- Type
- journal article
- Language
- en
- Update notices
- erratum (2005-05-05)
- Open access
- green
- europepmc.org
- Licence
- Locations
- The EMBO Journal (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- IRIS Research product catalog (Sapienza University of Rome) (submittedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Retinoids in leukemia and cellular processes
- Health Sciences › Medicine › Hematology › Acute Myeloid Leukemia Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chromatin Remodeling and Cancer
- Keywords
- AML1-ETO, PML-RARα, corepressor binding, NCoR, SMRT, histone deacetylase complex, transcriptional repression, myeloid differentiation, vitamin D3, retinoic acid, proteasomal degradation, cell-penetrating peptides, acute myeloid leukemia, differentiation therapy
- MeSH terms
- RUNX1 Translocation Partner 1 Protein, Acute Disease, Cell Differentiation, Cholecalciferol, DNA-Binding Proteins, Humans, Leukemia, Myeloid, Neoplasm Proteins, Nuclear Proteins, Peptides, Repressor Proteins, Transcription Factors, Tretinoin, Oncogene Proteins, Fusion, Gene Expression Regulation, Neoplastic, Protein Structure, Tertiary, Cell Line, Tumor, Core Binding Factor Alpha 2 Subunit, Nuclear Receptor Co-Repressor 1, Nuclear Receptor Co-Repressor 2
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