title: RARα2 expression confers myeloma stem cell features.
abstract: We previously demonstrated that RARα2 expression is increased in CD138 selected plasma cells of relapsed multiple myelomas (MMs), and increased expression was linked to poor prognosis in newly diagnosed MM patients. In the present study, we demonstrate that increased RARα2 confers myeloma stem cell features. Higher expression of RARα2 was identified in the multiple myeloma stem cell (MMSC) fraction. Overexpression of RARα2 in bulk MM cell lines resulted in: 1) increased drug resistance; 2) increased clonogenic potential; 3) activation of both Wnt and Hedgehog (Hh) pathways; 4) increased side population and aldehyde dehydrogenase levels; and 5) increased expression of embryonic stem cell genes. The opposite effects were seen with RARα2 knockdown. We demonstrate that RARα2 induces drug resistance by activating the drug efflux pump gene ABCC3 and anti-apoptotic Bcl-2 family members. Inhibition of Wnt signaling or ABCC3 function could overcome drug resistance in RARα2 overexpressing MM cells. We also showed that in the 5TGM1 mouse model, targeting of the Wnt and Hh pathways using CAY10404, cyclopamine, or itraconazole significantly reduced the myeloma tumor burden and increased survival. Targeting RARα2 or its downstream signaling pathways provides a potential strategy to eliminate MMSC.
authors.affiliation: Department of Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA.
authors.forename: Ye
authors.initials: Y
authors.lastname: Yang
authors.forename: Jumei
authors.initials: J
authors.lastname: Shi
authors.forename: Giulia
authors.initials: G
authors.lastname: Tolomelli
authors.forename: Hongwei
authors.initials: H
authors.lastname: Xu
authors.forename: Jiliang
authors.initials: J
authors.lastname: Xia
authors.forename: He
authors.initials: H
authors.lastname: Wang
authors.forename: Wen
authors.initials: W
authors.lastname: Zhou
authors.forename: Yi
authors.initials: Y
authors.lastname: Zhou
authors.forename: Satyabrata
authors.initials: S
authors.lastname: Das
authors.forename: Zhimin
authors.initials: Z
authors.lastname: Gu
authors.forename: Dana
authors.initials: D
authors.lastname: Levasseur
authors.forename: Fenghuang
authors.initials: F
authors.lastname: Zhan
authors.forename: Guido
authors.initials: G
authors.lastname: Tricot
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D002470:Cell Survival; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D053823:Hedgehog Proteins / Q000378:metabolism; D006801:Humans; D007555:Isoxazoles / Q000494:pharmacology; D017964:Itraconazole / Q000494:pharmacology; D051379:Mice; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000378:metabolism; D009101:Multiple Myeloma / Q000378:metabolism*; D014411:Neoplastic Stem Cells / Q000166:cytology*; D010950:Plasma Cells / Q000378:metabolism; D011379:Prognosis; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D018168:Receptors, Retinoic Acid / Q000378:metabolism*; D000072482:Retinoic Acid Receptor alpha; D015398:Signal Transduction; D013450:Sulfones / Q000494:pharmacology; D053668:Syndecan-1 / Q000378:metabolism; D014704:Veratrum Alkaloids / Q000494:pharmacology; D051153:Wnt Proteins / Q000378:metabolism
chemical_list: D053823:Hedgehog Proteins; D007555:Isoxazoles; D017964:Itraconazole; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D018168:Receptors, Retinoic Acid; D000072482:Retinoic Acid Receptor alpha; D013450:Sulfones; D053668:Syndecan-1; D014704:Veratrum Alkaloids; D051153:Wnt Proteins; C501048:3-(4-methylsulfonylphenyl)-4-phenyl-5-trifluoromethylisoxazole; C000607071:RARA protein, human; C000607072:Rara protein, mouse; C114462:multidrug resistance-associated protein 3; C000541:cyclopamine