title: Recruitment of RXR by homotetrameric RARalpha fusion proteins is essential for transformation.
abstract: While formation of higher-order oncogenic transcriptional complexes is critical for RARalpha fusion proteins in acute promyelocytic leukemia, the essential components and their roles in mediating transformation are still largely unknown. To this end, the present study demonstrates that homodimerization is not sufficient for RARalpha fusion-mediated transformation, which requires higher-order homotetramerization. Surprisingly, intrinsic homo-oligomeric DNA binding by the fusion proteins is also dispensable. Importantly, higher-order RXR/RARalpha fusion hetero-oligomeric complexes that aberrantly recruit transcriptional corepressors to downstream targets are essential for transformation. Intervention of RXR-dependent pathways by panRXR-agonists or RXRalpha shRNAs suppresses RARalpha fusion-mediated transformation. Taken together, these results define the oncogenic threshold for self-association and reveal the pathological significance of higher-order RARalpha fusion/RXR hetero-oligomeric complexes and their potential value as a therapeutic target.
authors.affiliation: Haemato-Oncology Section, The Institute of Cancer Research, 15 Cotswold Road, Sutton, Greater London SM2 5NG, UK.
authors.forename: Bernd B
authors.initials: BB
authors.lastname: Zeisig
authors.forename: Colin
authors.initials: C
authors.lastname: Kwok
authors.forename: Arthur
authors.initials: A
authors.lastname: Zelent
authors.forename: Pattabhiraman
authors.initials: P
authors.lastname: Shankaranarayanan
authors.forename: Hinrich
authors.initials: H
authors.lastname: Gronemeyer
authors.forename: Shuo
authors.initials: S
authors.lastname: Dong
authors.forename: Chi Wai Eric
authors.initials: CW
authors.lastname: So
mesh_terms: D001704:Biopolymers; D002471:Cell Transformation, Neoplastic; D018168:Receptors, Retinoic Acid / Q000737:chemistry / Q000502:physiology*; D011993:Recombinant Fusion Proteins / Q000378:metabolism*; D000072482:Retinoic Acid Receptor alpha; D047490:Retinoid X Receptor alpha / Q000502:physiology*; D050799:STAT5 Transcription Factor / Q000502:physiology
chemical_list: D001704:Biopolymers; D018168:Receptors, Retinoic Acid; D011993:Recombinant Fusion Proteins; D000072482:Retinoic Acid Receptor alpha; D047490:Retinoid X Receptor alpha; D050799:STAT5 Transcription Factor