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Blood, 16 July 2009, Vol. 114, No. 3, pp. 600-607. Prepublished online as a Blood First Edition Paper on May 20, 2009; DOI 10.1182/blood-2008-12-194126. This Article Full Text Full Text (PDF) Supplemental Tables All Versions of this Article: blood-2008-12-194126v1 114/3/600    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via CrossRef Google Scholar Articles by Wang, S. Articles by Zhan, F. PubMed PubMed Citation Articles by Wang, S. Articles by Zhan, F. Related Collections Lymphoid Neoplasia Clinical Trials and Observations Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  LYMPHOID NEOPLASIA RAR2 expression is associated with disease progression and plays a crucial role in efficacy of ATRA treatment in myeloma Siqing Wang13, Guido Tricot2,3, Lei Shi13, Wei Xiong13, Zhaoyang Zeng2,3, Hongwei Xu13, Maurizio Zangari2,3, Bart Barlogie1, John D. Shaughnessy, Jr1, and Fenghuang Zhan13 1 The Donna D. and Donald M. Lambert Laboratory of Myeloma Genetics at the Myeloma Institute for Research and Therapy, University of Arkansas for Medical Sciences, Little Rock; and 2 Division of Hematology/BMT/Myeloma Program, School of Medicine and 3 Huntsman Cancer Institute, University of Utah, Salt Lake City Specific genetic alterations in multiple myeloma (MM) may cause more aggressive diseases. Paired gene array analysis on 51 samples showed that retinoic acid (RA) receptor (RAR) expression significantly increased at relapse compared with diagnosis. RAR encodes 2 major isoforms: RAR1 and RAR2. In this study, we examined the function of RAR2 in MM. Reverse transcription–polymerase chain reaction (RT-PCR) revealed ubiquitous RAR1 expression in MM cells, but RAR2 was expressed in 26 (32%) of 80 newly diagnosed patients and 10 (28%) of 36 MM cell lines. Patients with RAR2 expression had a significantly shorter overall survival on identical treatments. The presence of RAR2 remained significant on multivariate analysis. Knockdown of RAR2 but not RAR1 induced significant MM cell death and growth inhibition, and overexpressing RAR2 activated STAT3 and mitogen-activated protein kinase kinase (MEK)/extracellular signal–regulated kinase (ERK) signaling pathways. Interestingly, all-trans retinoic acid (ATRA) treatment induced potent cell death and growth inhibition in RAR2+ but not RAR2– MM cells; overexpressing RAR2 in RAR2-deficient MM cells restored sensitivity to ATRA. Furthermore, ATRA treatment significantly inhibited the growth of RAR2-overexpressing MM tumors in severe combined immunodeficiency (SCID) mouse model. These findings provide a rationale for RA-based therapy in aggressive RAR2+ MM. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

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