title: Targeting fusion protein/corepressor contact restores differentiation response in leukemia cells.
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.
authors.affiliation: Patologia Generale and Medicina Interna e Scienze Oncologiche, Dipartimento di Medicina Clinica e Sperimentale, Perugia University, Policlinico Monteluce, Perugia, Italy.
authors.forename: Serena
authors.initials: S
authors.lastname: Racanicchi
authors.forename: Chiara
authors.initials: C
authors.lastname: Maccherani
authors.forename: Concetta
authors.initials: C
authors.lastname: Liberatore
authors.forename: Monia
authors.initials: M
authors.lastname: Billi
authors.forename: Vania
authors.initials: V
authors.lastname: Gelmetti
authors.forename: Maddalena
authors.initials: M
authors.lastname: Panigada
authors.forename: Giovanni
authors.initials: G
authors.lastname: Rizzo
authors.forename: Clara
authors.initials: C
authors.lastname: Nervi
authors.forename: Francesco
authors.initials: F
authors.lastname: Grignani
mesh_terms: D000208:Acute Disease; D002454:Cell Differentiation / Q000187:drug effects; D045744:Cell Line, Tumor; D002762:Cholecalciferol / Q000494:pharmacology; D050676:Core Binding Factor Alpha 2 Subunit; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D007951:Leukemia, Myeloid / Q000378:metabolism*; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D056971:Nuclear Receptor Co-Repressor 1; D056985:Nuclear Receptor Co-Repressor 2; D015514:Oncogene Proteins, Fusion / Q000235:genetics / Q000378:metabolism*; D010455:Peptides / Q000235:genetics / Q000502:physiology; D017434:Protein Structure, Tertiary / Q000235:genetics / Q000502:physiology; D000075142:RUNX1 Translocation Partner 1 Protein; D012097:Repressor Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014212:Tretinoin / Q000494:pharmacology
chemical_list: C107844:AML1-ETO fusion protein, human; D050676:Core Binding Factor Alpha 2 Subunit; D004268:DNA-Binding Proteins; C539127:NCOR1 protein, human; C539130:NCOR2 protein, human; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D056971:Nuclear Receptor Co-Repressor 1; D056985:Nuclear Receptor Co-Repressor 2; D015514:Oncogene Proteins, Fusion; D010455:Peptides; D000075142:RUNX1 Translocation Partner 1 Protein; D012097:Repressor Proteins; D014157:Transcription Factors; C093476:promyelocytic leukemia-retinoic acid receptor alpha fusion oncoprotein; D002762:Cholecalciferol; D014212:Tretinoin
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