RARα2 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 α (RARα) expression significantly increased at relapse compared with diagnosis. RARα encodes 2 major isoforms: RARα1 and RARα2. In this study, we examined the function of RARα2 in MM. Reverse transcription-polymerase chain reaction (RT-PCR) revealed ubiquitous RARα1 expression in MM cells, but RARα2 was expressed in 26 (32%) of 80 newly diagnosed patients and 10 (28%) of 36 MM cell lines. Patients with RARα2 expression had a significantly shorter overall survival on identical treatments. The presence of RARα2 remained significant on multivariate analysis. Knockdown of RARα2 but not RARα1 induced significant MM cell death and growth inhibition, and overexpressing RARα2 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 RARα2⁺ but not RARα2 ^- MM cells; overexpressing RARα2 in RARα2-deficient MM cells restored sensitivity to ATRA. Furthermore, ATRA treatment significantly inhibited the growth of RARα2-overexpressing MM tumors in severe combined immunodeficiency (SCID) mouse model. These findings provide a rationale for RA-based therapy in aggressive RARα2⁺ MM.