RARalpha2 expression is associated with disease progression and plays a crucial role in efficacy of ATRA treatment in myeloma.
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.
Wang
Siqing
S
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.
Tricot
Guido
G
Shi
Lei
L
Xiong
Wei
W
Zeng
Zhaoyang
Z
Xu
Hongwei
H
Zangari
Maurizio
M
Barlogie
Bart
B
Shaughnessy
John D
JD
Zhan
Fenghuang
F
D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D018450:Disease Progression; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D020869:Gene Expression Profiling; D006801:Humans; D008297:Male; D051379:Mice; D016513:Mice, SCID; D009101:Multiple Myeloma / Q000737:chemistry* / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D011237:Predictive Value of Tests; D020033:Protein Isoforms; D018168:Receptors, Retinoic Acid / Q000032:analysis / Q000172:deficiency / Q000235:genetics*; D012008:Recurrence; D000072482:Retinoic Acid Receptor alpha; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction; D015996:Survival Rate; D014212:Tretinoin / Q000494:pharmacology* / Q000627:therapeutic use; D014407:Tumor Cells, Cultured
D020033:Protein Isoforms; C000607071:RARA protein, human; C000607072:Rara protein, mouse; D018168:Receptors, Retinoic Acid; D000072482:Retinoic Acid Receptor alpha; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D014212:Tretinoin