title: Bortezomib resistance can be reversed by induced expression of plasma cell maturation markers in a mouse in vitro model of multiple myeloma.
abstract: Multiple myeloma (MM), the second most common hematopoietic malignancy, remains an incurable plasma cell (PC) neoplasm. While the proteasome inhibitor, bortezomib (Bz) has increased patient survival, resistance represents a major treatment obstacle as most patients ultimately relapse becoming refractory to additional Bz therapy. Current tests fail to detect emerging resistance; by the time patients acquire resistance, their prognosis is often poor. To establish immunophenotypic signatures that predict Bz sensitivity, we utilized Bz-sensitive and -resistant cell lines derived from tumors of the Bcl-X(L)/Myc mouse model of PC malignancy. We identified significantly reduced expression of two markers (CD93, CD69) in "acquired" (Bz-selected) resistant cells. Using this phenotypic signature, we isolated a subpopulation of cells from a drug-naïve, Bz-sensitive culture that displayed "innate" resistance to Bz. Although these genes were identified as biomarkers, they may indicate a mechanism for Bz-resistance through the loss of PC maturation which may be induced and/or selected by Bz. Significantly, induction of PC maturation in both "acquired" and "innate" resistant cells restored Bz sensitivity suggesting a novel therapeutic approach for reversing Bz resistance in refractory MM.
authors.affiliation: Department of Genetics, Cell Biology and Development, University of Minnesota, Minneapolis, Minnesota, United States of America.
authors.forename: Holly A F
authors.initials: HA
authors.lastname: Stessman
authors.forename: Aatif
authors.initials: A
authors.lastname: Mansoor
authors.forename: Fenghuang
authors.initials: F
authors.lastname: Zhan
authors.forename: Michael A
authors.initials: MA
authors.lastname: Linden
authors.forename: Brian
authors.initials: B
authors.lastname: Van Ness
authors.forename: Linda B
authors.initials: LB
authors.lastname: Baughn
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D000945:Antigens, Differentiation, T-Lymphocyte / Q000378:metabolism; D015415:Biomarkers / Q000378:metabolism; D001897:Boronic Acids / Q000494:pharmacology*; D000069286:Bortezomib; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm / Q000502:physiology; D006801:Humans; D037181:Lectins, C-Type / Q000378:metabolism; D051379:Mice; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology*; D010950:Plasma Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D011719:Pyrazines / Q000494:pharmacology*; D000099192:CD69 Antigens
chemical_list: D015703:Antigens, CD; D000945:Antigens, Differentiation, T-Lymphocyte; D015415:Biomarkers; D001897:Boronic Acids; D000069286:Bortezomib; D037181:Lectins, C-Type; D011719:Pyrazines; D000099192:CD69 Antigens