title: Critical role of retinoid/rexinoid signaling in mediating transformation and therapeutic response of NUP98-RARG leukemia.
abstract: While the nucleoporin 98-retinoic acid receptor gamma (NUP98-RARG) is the first RARG fusion protein found in acute leukemia, its roles and the molecular basis in oncogenic transformation are currently unknown. Here, we showed that homodimeric NUP98-RARG not only acquired unique nuclear localization pattern and ability of recruiting both RXRA and wild-type NUP98, but also exhibited similar transcriptional properties as RARA fusions found in acute promyelocytic leukemia (APL). Using murine bone marrow retroviral transduction/transformation assay, we further demonstrated that NUP98-RARG fusion protein had gained transformation ability of primary hematopoietic stem/progenitor cells, which was critically dependent on the C-terminal GLFG domain of NUP98 and the DNA binding domain (DBD) of RARG. In contrast to other NUP98 fusions, cells transformed by the NUP98-RARG fusion were extremely sensitive to all-trans retinoic acid (ATRA) treatment. Interestingly, while pan-RXR agonists, SR11237 and LGD1069 could specifically inhibit NUP98-RARG transformed cells, mutation of the RXR interaction domain in NUP98-RARG had little effect on its transformation, revealing that therapeutic functions of rexinoid can be independent of the direct biochemical interaction between RXR and the fusion. Together, these results indicate that deregulation of the retinoid/rexinoid signaling pathway has a major role and may represent a potential therapeutic target for NUP98-RARG-mediated transformation.
authors.affiliation: 1] Department of Medicine, Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX, USA [2] Department of Pathology and Laboratory Medicine, Temple University School of Medicine, Philadelphia, PA, USA.
authors.forename: J J
authors.initials: JJ
authors.lastname: Qiu
authors.affiliation: King's College London, Leukaemia and Stem Cell Biology Group, Department of Haematologial Medicine, London UK.
authors.forename: B B
authors.initials: BB
authors.lastname: Zeisig
authors.affiliation: 1] Department of Medicine, Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX, USA [2] Department of Oncology, Xijing Hospital, The Fourth Military Medical University, Xi'an, Shaanxi, China.
authors.forename: S
authors.initials: S
authors.lastname: Li
authors.affiliation: Department of Oncology, Xijing Hospital, The Fourth Military Medical University, Xi'an, Shaanxi, China.
authors.forename: W
authors.initials: W
authors.lastname: Liu
authors.affiliation: Department of Medicine, Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX, USA.
authors.forename: H
authors.initials: H
authors.lastname: Chu
authors.affiliation: Department of Pharmacology, Baylor College of Medicine, Houston, TX, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Song
authors.affiliation: 1] Sbarro Institute for Cancer Research and Molecular Medicine & Center for Biotechology, Temple University, Philadelphia, PA, USA [2] Department of Medicine, Surgery & Neuroscience, University of Siena, Siena, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Giordano
authors.affiliation: University Children's Hospital Basel (UKBB), Department of Biomedicine, Hebelstrasse 20, CH-4031 Basel, Switzerland.
authors.forename: J
authors.initials: J
authors.lastname: Schwaller
authors.affiliation: Equipe Labellisée Ligue Contre le Cancer, Department of Functional Genomics and Cancer, Institut Génétique de Biologie Moléculaire et Cellulaire (IGBMC), CNRS/INSERM/UdS/CERBM, C.U. de Strasbourg, BP 10142, Illkirch-Cedex, France.
authors.forename: H
authors.initials: H
authors.lastname: Gronemeyer
authors.affiliation: Department of Medicine, Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX, USA.
authors.forename: S
authors.initials: S
authors.lastname: Dong
authors.affiliation: King's College London, Leukaemia and Stem Cell Biology Group, Department of Haematologial Medicine, London UK.
authors.forename: C W E
authors.initials: CW
authors.lastname: So
mesh_terms: D000818:Animals; D002467:Cell Nucleus / Q000378:metabolism; D002471:Cell Transformation, Neoplastic; D015973:Gene Expression Regulation, Leukemic; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D007938:Leukemia / Q000378:metabolism*; D051379:Mice; D008856:Microscopy, Fluorescence; D028861:Nuclear Pore Complex Proteins / Q000378:metabolism*; D011485:Protein Binding; D025941:Protein Interaction Mapping; D055503:Protein Multimerization; D017434:Protein Structure, Tertiary; D018168:Receptors, Retinoic Acid / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D012190:Retroviridae / Q000235:genetics; D015398:Signal Transduction; D014212:Tretinoin / Q000737:chemistry; D000097768:Retinoic Acid Receptor gamma
chemical_list: D028861:Nuclear Pore Complex Proteins; D018168:Receptors, Retinoic Acid; D011993:Recombinant Fusion Proteins; D014212:Tretinoin; D000097768:Retinoic Acid Receptor gamma; C093350:nuclear pore complex protein 98