Wang Siqing, Tricot Guido, Shi Lei, Xiong Wei, Zeng Zhaoyang, Xu Hongwei, Zangari Maurizio, Barlogie Bart, Shaughnessy John D, Zhan Fenghuang
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, 4301 W Markham, Little Rock, AR, USA.
Blood. 2009 Jul 16;114(3):600-7. doi: 10.1182/blood-2008-12-194126. Epub 2009 May 20.
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 alpha (RARalpha) expression significantly increased at relapse compared with diagnosis. RARalpha encodes 2 major isoforms: RARalpha1 and RARalpha2. In this study, we examined the function of RARalpha2 in MM. Reverse transcription-polymerase chain reaction (RT-PCR) revealed ubiquitous RARalpha1 expression in MM cells, but RARalpha2 was expressed in 26 (32%) of 80 newly diagnosed patients and 10 (28%) of 36 MM cell lines. Patients with RARalpha2 expression had a significantly shorter overall survival on identical treatments. The presence of RARalpha2 remained significant on multivariate analysis. Knockdown of RARalpha2 but not RARalpha1 induced significant MM cell death and growth inhibition, and overexpressing RARalpha2 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 RARalpha2(+) but not RARalpha2(-) MM cells; overexpressing RARalpha2 in RARalpha2-deficient MM cells restored sensitivity to ATRA. Furthermore, ATRA treatment significantly inhibited the growth of RARalpha2-overexpressing MM tumors in severe combined immunodeficiency (SCID) mouse model. These findings provide a rationale for RA-based therapy in aggressive RARalpha2(+) MM.
多发性骨髓瘤（MM）中的特定基因改变可能导致疾病更具侵袭性。对51个样本进行的配对基因阵列分析显示，与诊断时相比，复发时维甲酸（RA）受体α（RARα）表达显著增加。RARα编码2种主要异构体：RARα1和RARα2。在本研究中，我们检测了RARα2在MM中的功能。逆转录-聚合酶链反应（RT-PCR）显示MM细胞中普遍存在RARα1表达，但80例新诊断患者中有26例（32%）和36株MM细胞系中有10例（28%）表达RARα2。RARα2表达的患者在相同治疗下总生存期显著缩短。在多变量分析中，RARα2的存在仍然具有显著性。敲低RARα2而非RARα1可诱导显著的MM细胞死亡和生长抑制，过表达RARα2可激活STAT3和丝裂原活化蛋白激酶激酶（MEK）/细胞外信号调节激酶（ERK）信号通路。有趣的是，全反式维甲酸（ATRA）处理在RARα2（+）而非RARα2（-）的MM细胞中诱导了有效的细胞死亡和生长抑制；在RARα2缺陷的MM细胞中过表达RARα2可恢复对ATRA的敏感性。此外，ATRA处理在严重联合免疫缺陷（SCID）小鼠模型中显著抑制了RARα2过表达的MM肿瘤生长。这些发现为侵袭性RARα2（+）MM的基于RA的治疗提供了理论依据。
