title: Multiple myeloma cells expressing low levels of CD138 have an immature             phenotype and reduced sensitivity to lenalidomide.
abstract: CD138 expression is a hallmark of plasma cells and multiple myeloma cells.             However, decreased expression of CD138 is frequently observed in plasma cells             of myeloma patients, although the clinical significance of this is unclear. To             evaluate the significance of low expression of CD138 in MM, we examined the phenotypes             of MM cells expressing low levels of CD138. Flow cytometric analysis of primary             MM cells revealed a significant decrease in CD138 expression in patients with             relapsed/progressive disease compared with untreated MM patients. Patients with             low levels of CD138 had a worse overall survival compared with patients with high             levels of CD138, in newly diagnosed patients and patients receiving high-dose             chemotherapy followed by autologous stem-cell transplantation. Two MM cell lines,             KYMM-1 (CD138- low) and KYMM-2 (CD138- high), were established from a single MM             patient with decreased CD138 expression. High expression of BCL6 and PAX5, and             downregulation of IRF4, PRDM1 and XBP1 was observed in KYMM-1 compared with KYMM-2             cells, indicative of the immature phenotype of KYMM-1. KYMM-1 was less sensitive             to lenalidomide than KYMM-2, while no difference in sensitivity to bortezomib             was observed. KYMM-2 cells were further divided in CD138+ and CD138- fractions             using anti-CD138-coated magnetic beads. CD138- cells sorted from the KYMM-2 cell             line also showed high BCL6, low IRF4 expression and decreased sensitivity to lenalidomide             compared with CD138+ cells. Our observations suggest that low CD138 expression             relates to i) poor prognosis, ii) immature phenotype and iii) low sensitivity             to lenalidomide. The observed distinct characteristics of CD138 low MM cells,             suggest this should be recognized as a new clinical entity. Establishment of a             treatment strategy for MM cells expressing low levels of CD138 is needed to improve             their poor outcome.
authors: Department of Hematology, Kumamoto University School of Medicine,                     Kumamoto, Japan.
authors: Yawara
authors: Y
authors: Kawano
authors: Shiho
authors: S
authors: Fujiwara
authors: Naoko
authors: N
authors: Wada
authors: Mikiko
authors: M
authors: Izaki
authors: Hiromichi
authors: H
authors: Yuki
authors: Yutaka
authors: Y
authors: Okuno
authors: Kenichi
authors: K
authors: Iyama
authors: Hiroshi
authors: H
authors: Yamasaki
authors: Akira
authors: A
authors: Sakai
authors: Hiroaki
authors: H
authors: Mitsuya
authors: Hiroyuki
authors: H
authors: Hata
mesh_terms: D000368:Aged; D017209:Apoptosis; D014408:Biomarkers, Tumor; D001897:Boronic Acids / Q000494:pharmacology; D000069286:Bortezomib; D045744:Cell Line, Tumor; D019175:DNA Methylation; D004268:DNA-Binding Proteins / Q000378:metabolism; D019008:Drug Resistance, Neoplasm; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D050835:Interferon Regulatory Factors / Q000378:metabolism; D000077269:Lenalidomide; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000378:metabolism*; D051757:PAX5 Transcription Factor / Q000378:metabolism; D010641:Phenotype; D000074462:Positive Regulatory Domain I-Binding Factor 1; D011379:Prognosis; D051560:Proto-Oncogene Proteins c-bcl-6; D011719:Pyrazines / Q000494:pharmacology; D000071701:Regulatory Factor X Transcription Factors; D012097:Repressor Proteins / Q000378:metabolism; D053668:Syndecan-1 / Q000378:metabolism*; D013792:Thalidomide / Q000031:analogs & derivatives* / Q000494:pharmacology; D014157:Transcription Factors / Q000378:metabolism; D000071717:X-Box Binding Protein 1; D000099218:Interferon Regulatory Factor-4
chemical_list: D014408:Biomarkers, Tumor; D001897:Boronic Acids; D000069286:Bortezomib; D004268:DNA-Binding Proteins; D050835:Interferon Regulatory Factors; D000077269:Lenalidomide; D051757:PAX5 Transcription Factor; D000074462:Positive Regulatory Domain I-Binding Factor 1; D051560:Proto-Oncogene Proteins c-bcl-6; D011719:Pyrazines; D000071701:Regulatory Factor X Transcription Factors; D012097:Repressor Proteins; D053668:Syndecan-1; D013792:Thalidomide; D014157:Transcription Factors; D000071717:X-Box Binding Protein 1; D000099218:Interferon Regulatory Factor-4; C084103:BCL6 protein, human; C497281:PAX5 protein, human; C000605543:XBP1 protein, human; C087042:PRDM1 protein, human