title: Lenalidomide targets clonogenic side population in multiple myeloma: pathophysiologic and clinical implications.
abstract: Recurrence of multiple myeloma (MM) after therapy suggests the presence of tumor-initiating subpopulations. In our study, we performed flow cytometry-based Hoechst 33342 staining to evaluate the existence of a MM population with stem-like features known as side population (SP) cells. SP cells exhibit substantial heterogeneity in MM cell lines and primary MM cells; express CD138 antigen in MM cell lines; display higher mRNA expression and functional activity of ABCG2 transporter; and have a higher proliferation index compared with non-SP cells. We observed evidence for clonogenic potential of SP cells, as well as the ability of SP cells to regenerate original population. Moreover, SP cells revealed higher tumorigenicity compared with non-SP cells. Importantly, lenalidomide decreased the percentage and clonogenicity of SP cells, and also induced phosphorylation changes in Akt, GSK-3α/β, MEK1, c-Jun, p53, and p70S6K in SP cells. Adherence to bone marrow stromal cells (BMSCs) increased the percentage, viability, and proliferation potential of SP cells. Lenalidomide and thalidomide abrogated this stimulatory effect of BMSCs and significantly decreased the percentage of SP cells. Our studies demonstrate a novel mechanism of action for lenalidomide, namely targeting SP fraction, providing the framework for new therapeutic strategies targeting subpopulations of MM cells including presumptive stem cells.
authors.affiliation: Jerome Lipper Multiple Myeloma Center, Dana-Farber Cancer Institute, Department of Medical Oncology, Boston, MA, USA.
authors.forename: Jana
authors.initials: J
authors.lastname: Jakubikova
authors.forename: Sophia
authors.initials: S
authors.lastname: Adamia
authors.forename: Maria
authors.initials: M
authors.lastname: Kost-Alimova
authors.forename: Steffen
authors.initials: S
authors.lastname: Klippel
authors.forename: David
authors.initials: D
authors.lastname: Cervi
authors.forename: John F
authors.initials: JF
authors.lastname: Daley
authors.forename: Dana
authors.initials: D
authors.lastname: Cholujova
authors.forename: Sun-Young
authors.initials: SY
authors.lastname: Kong
authors.forename: Merav
authors.initials: M
authors.lastname: Leiba
authors.forename: Simona
authors.initials: S
authors.lastname: Blotta
authors.forename: Melissa
authors.initials: M
authors.lastname: Ooi
authors.forename: Jake
authors.initials: J
authors.lastname: Delmore
authors.forename: Jacob
authors.initials: J
authors.lastname: Laubach
authors.forename: Paul G
authors.initials: PG
authors.lastname: Richardson
authors.forename: Jan
authors.initials: J
authors.lastname: Sedlak
authors.forename: Kenneth C
authors.initials: KC
authors.lastname: Anderson
authors.forename: Constantine S
authors.initials: CS
authors.lastname: Mitsiades
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000235:genetics; D020533:Angiogenesis Inhibitors / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001854:Bone Marrow Cells / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D002455:Cell Division / Q000187:drug effects; D002458:Cell Fractionation; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D003114:Colony-Forming Units Assay; D019008:Drug Resistance, Neoplasm; D006801:Humans; D000077269:Lenalidomide; D009101:Multiple Myeloma / Q000188:drug therapy / Q000473:pathology / Q000503:physiopathology; D009364:Neoplasm Recurrence, Local / Q000517:prevention & control; D014411:Neoplastic Stem Cells / Q000187:drug effects* / Q000473:pathology; D015398:Signal Transduction / Q000187:drug effects; D017154:Stromal Cells / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D053668:Syndecan-1 / Q000378:metabolism; D013792:Thalidomide / Q000031:analogs & derivatives* / Q000494:pharmacology
chemical_list: D018528:ATP-Binding Cassette Transporters; D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; C508241:SDC1 protein, human; D053668:Syndecan-1; D013792:Thalidomide; D000077269:Lenalidomide