Submitted December 11, 2008
Accepted May 12, 2009
RAR
2 expression is associated with disease progression and plays a crucial role in efficacy of ATRA treatment in myeloma
Siqing Wang, Guido Tricot, Lei Shi, Wei Xiong, Zhaoyang Zeng, Hongwei Xu, Maurizio Zangari, Bart Barlogie, John D. Shaughnessy Jr, and Fenghuang Zhan*
The Donna D. and Donald M. Lambert Laboratory of Myeloma Genetics, the Myeloma Institute for Research and Therapy, University of Arkansas for Medical Sciences, Little Rock, AR, United States
Division of Hematology/BMT/myeloma Program, University of Utah School of Medicine, Salt Lake City, UT, United States
Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, United States
* Corresponding author; email: fenghuang.zhan{at}hsc.utah.edu.
Multiple myeloma (MM) remains largely incurable. Specific genetic alterations 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 to diagnosis. RAR encodes two major isoforms: RAR1 and RAR2. In this study, we examined the function of RAR2 in MM. RT-PCR revealed ubiquitous RAR1 expression in MM cells, but RAR2 was expressed in 26 of 80 (32%) newly diagnosed patients and 10 of 36 (28%) 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 over-expressing RAR2 activated STAT3 and MEK/ERK signaling pathways. These results demonstrated a crucial role of RAR2, but not RAR1 in MM cell growth and disease progression. Interestingly, ATRA treatment induced potent cell death and growth inhibition in RAR2-positive but not RAR2-negative MM cells; over-expressing RAR2 in RAR2-deficient MM cells restored sensitivity to ATRA. Furthermore, ATRA-treatment significantly inhibited the growth of RAR2-overexpressing MM tumors in SCID mouse model. These findings provide a rationale for RA-based therapy in aggressive RAR2-positive MM.
