title: The self-association coiled-coil domain of PML is sufficient for the oncogenic conversion of the retinoic acid receptor (RAR) alpha.
abstract: In acute promyelocytic leukemia (APL) the retinoic acid receptor alpha (RARα) becomes an oncogene through the fusion with several partners, mostly with promyelocytic leukemia protein (PML), all of which have in common the presence of a self-association domain. The new fusion proteins, therefore, differently from the wild-type RARα, which forms only heterodimers with retinoic X receptor alpha, are also able to homo-oligomerize. The presence of such a domain has been suggested to be crucial for the leukemogenic potential of the chimeric proteins found in APL blasts. Whether or not any self-association domain is sufficient to bestow a leukemogenic activity on RARα is still under investigation. In this work, we address this question using two different X-RARα chimeras, where X represents the coiled-coil domain of PML (CC-RARα) or the oligomerization portion of the yeast transcription factor GCN4 (GCN4-RARα). We demonstrate that in vitro both proteins have transforming potential, and recapitulate the main PML-RARα biological properties, but CC-RARα is uniquely able to disrupt PML nuclear bodies. Indeed, in vivo only the CC-RARα chimera induces efficiently APL in a murine transplantation model. Thus, the PML CC domain represents the minimal structural determinant indispensable to transform RARα into an oncogenic protein.
authors.affiliation: Department of Experimental Oncology, IFOM-IEO Campus, Milan, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Occhionorelli
authors.forename: F
authors.initials: F
authors.lastname: Santoro
authors.forename: I
authors.initials: I
authors.lastname: Pallavicini
authors.forename: A
authors.initials: A
authors.lastname: Gruszka
authors.forename: S
authors.initials: S
authors.lastname: Moretti
authors.forename: D
authors.initials: D
authors.lastname: Bossi
authors.forename: A
authors.initials: A
authors.lastname: Viale
authors.forename: D
authors.initials: D
authors.lastname: Shing
authors.forename: S
authors.initials: S
authors.lastname: Ronzoni
authors.forename: I
authors.initials: I
authors.lastname: Muradore
authors.forename: M
authors.initials: M
authors.lastname: Soncini
authors.forename: G
authors.initials: G
authors.lastname: Pruneri
authors.forename: P
authors.initials: P
authors.lastname: Rafaniello
authors.forename: G
authors.initials: G
authors.lastname: Viale
authors.forename: P G
authors.initials: PG
authors.lastname: Pelicci
authors.forename: S
authors.initials: S
authors.lastname: Minucci
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002471:Cell Transformation, Neoplastic; D002850:Chromatography, Gel; D005455:Fluorescent Antibody Technique; D006412:Hematopoietic Stem Cells / Q000378:metabolism; D016130:Immunophenotyping; D047468:Immunoprecipitation; D015473:Leukemia, Promyelocytic, Acute / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D009687:Nuclear Proteins / Q000235:genetics*; D000071156:Promyelocytic Leukemia Protein; D055503:Protein Multimerization; D012333:RNA, Messenger / Q000235:genetics; D018168:Receptors, Retinoic Acid / Q000235:genetics*; D011993:Recombinant Fusion Proteins / Q000502:physiology*; D000072482:Retinoic Acid Receptor alpha; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014157:Transcription Factors / Q000235:genetics*; D025521:Tumor Suppressor Proteins / Q000235:genetics*
chemical_list: D009687:Nuclear Proteins; C513293:Pml protein, mouse; D000071156:Promyelocytic Leukemia Protein; D012333:RNA, Messenger; C000607072:Rara protein, mouse; D018168:Receptors, Retinoic Acid; D011993:Recombinant Fusion Proteins; D000072482:Retinoic Acid Receptor alpha; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins