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Oncogenes, Fusion Genes and Tumor Suppressor Genes

Critical role of retinoid/rexinoid signaling in mediating transformation and therapeutic response of NUP98-RARG leukemia

Leukemia volume 29, pages 1153–1162 (2015)Cite this article

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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.

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Acknowledgements

We would like to thank Mr B Cao from Beijing Friendship Hospital Capital Medical University, Drs X Wang, L Sun, X Sun from Baylor College of Medicine and Mr SH Tung from King’s College London for their helpful discussion and inputs. We thank Dr X Xu (Department of Clinical Cancer Prevention, The University of Texas M D Anderson Cancer Center, Houston) for the RARG construct, Dr CD Allis (Laboratory of Chromatin Biology and Epigenetics, The Rockefeller University, New York) for NUP98-PHF23 and NUP98-JARID1A expression vectors, Dr AS Belmont (University of Illinois, Urbana) for the A03_1 cell line. This work was supported in part, by funds from the Albert and Margaret Alkek Foundation (SD), Leukemia Research Foundation (LRF) (SD), Ladies Leukemia League (LLL) (SD), the Cancer Prevention and Research Institute of Texas (CPRIT, RP110050; SD, YS and RP100421; JJQ, SD), Leukaemia and Lymphoma Research (LLR) (CWES), Cancer Research UK (CRUK) (CWES), and the Kay Kendall Leukaemia Fund (KKLF) (CWES).

Author Contributions

JJQ and BBZ designed and performed research and wrote the manuscript; SL performed research and wrote the manuscript; HC performed research; WL and YS analyzed data; AG, JS and HG contributed reagents, analyzed data and edited the paper; and SD and CWES designed research and wrote the manuscript.

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Author notes

  1. J J Qiu, B B Zeisig and S Li: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Medicine, Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX, USA

    J J Qiu, S Li, H Chu & S Dong

  2. Department of Pathology and Laboratory Medicine, Temple University School of Medicine, Philadelphia, PA, USA

    J J Qiu

  3. Department of Haematologial Medicine, King's College London, Leukaemia and Stem Cell Biology Group, London, UK

    B B Zeisig & C W E So

  4. Department of Oncology, Xijing Hospital, The Fourth Military Medical University, Xi'an, Shaanxi, China

    S Li & W Liu

  5. Department of Pharmacology, Baylor College of Medicine, Houston, TX, USA

    Y Song

  6. Sbarro Institute for Cancer Research and Molecular Medicine & Center for Biotechology, Temple University, Philadelphia, PA, USA

    A Giordano

  7. Department of Medicine, Surgery & Neuroscience, University of Siena, Siena, Italy

    A Giordano

  8. Department of Biomedicine, University Children's Hospital Basel (UKBB), Hebelstrasse 20, CH-4031 Basel, Switzerland

    J Schwaller

  9. Department of Functional Genomics and Cancer, Equipe Labellisée Ligue Contre le Cancer, Institut Génétique de Biologie Moléculaire et Cellulaire (IGBMC), CNRS/INSERM/UdS/CERBM, C.U. de Strasbourg, BP 10142, Illkirch-Cedex, France

    H Gronemeyer

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Qiu, J., Zeisig, B., Li, S. et al. Critical role of retinoid/rexinoid signaling in mediating transformation and therapeutic response of NUP98-RARG leukemia. Leukemia 29, 1153–1162 (2015). https://doi.org/10.1038/leu.2014.334

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