title: Identification of loss of p16 expression and upregulation of MDR-1 as genetic events resulting from two novel chromosomal translocations found in a plasmablastic lymphoma of the uterus.
abstract: OBJECTIVE
  To establish cell lines from the patient with plasmablastic lymphoma, who was immunologically competent including negative human immunodeficiency virus (HIV) serology, and analyze the unique chromosomal translocations seen in the cell lines in order to unveil the pathogenesis of this tumor, which had no evidence of Epstein-Barr virus involvement.
  
  
  METHODS
  Establishment of the cell lines was attempted by inoculating the patient's lymph node biopsy specimen subcutaneously to immunodeficient mice. Comparative genomic hybridization (CGH) array and FISH analysis were performed to identify breakpoints of the two chromosomal translocations. Of the 4 candidate genes identified by FISH analysis to be involved in the translocations, reverse transcription-PCR, Western blot, flow cytometry, and proliferation assay were performed to identify the exact genes involved.
  
  
  RESULTS
  Analysis of the cell lines identified loss of p16 at the protein level by chromosomal translocation of t(9;13) and upregulation of MDR-1 by t(4;7). The cell lines expressing MDR-1 acquired resistance to chemotherapeutic agents such as cisplatin and doxorubicin, but not bortezomib. Expression of B lymphoid lineage marker genes of these cell lines was negative for paired box 5 (Pax5) or PR domain containing 1, with ZNF domain (PRDM1), but was positive for X-box binding protein 1 (Xbp1).
  
  
  CONCLUSIONS
  We established three novel cell lines of plasmablastic lymphoma. Characterization of the unique chromosomal translocation identified loss of p16 and upregulation of MDR-1 at protein level. Expression of Xbp1(s), which is involved in the maturation of plasma cells, corresponded to the plasmablastic appearance of the tumor. These cell lines may be a useful tool to understand the pathophysiology of the disease and to develop novel treatment strategies.
authors.affiliation: Division of Hematology, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan. erie@kk.iij4u.or.jp
authors.forename: Eri
authors.initials: E
authors.lastname: Matsuki
authors.forename: Yoshitaka
authors.initials: Y
authors.lastname: Miyakawa
authors.forename: Shuichi
authors.initials: S
authors.lastname: Asakawa
authors.forename: Yuiko
authors.initials: Y
authors.lastname: Tsukada
authors.forename: Taketo
authors.initials: T
authors.lastname: Yamada
authors.forename: Kenji
authors.initials: K
authors.lastname: Yokoyama
authors.forename: Jun
authors.initials: J
authors.lastname: Kudoh
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Ikeda
authors.forename: Shinichiro
authors.initials: S
authors.lastname: Okamoto
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D015153:Blotting, Western; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D055028:Comparative Genomic Hybridization; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics* / Q000378:metabolism; D005260:Female; D005434:Flow Cytometry; D015972:Gene Expression Regulation, Neoplastic; D006367:HeLa Cells; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D008198:Lymph Nodes / Q000378:metabolism / Q000473:pathology / Q000637:transplantation; D016403:Lymphoma, Large B-Cell, Diffuse / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D008875:Middle Aged; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014178:Translocation, Genetic; D014183:Transplantation, Heterologous; D015854:Up-Regulation; D014594:Uterine Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D014599:Uterus / Q000378:metabolism / Q000473:pathology
chemical_list: C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D019941:Cyclin-Dependent Kinase Inhibitor p16