title: A tumor-related lymphoid progenitor population supports hierarchical tumor organization in canine B-cell lymphoma.
abstract: BACKGROUND
  Tumors have heterogeneous properties, which could be explained by the existence of hierarchically and biologically distinct tumor cells such as tumor-initiating cells (TICs). This model is clinically important, as TICs are promising targets for cancer therapies. However, TICs in spontaneous B-cell lymphoma have not been conclusively identified.
  
  
  OBJECTIVE
  Tumor cells with a progenitor phenotype exist in B-cell lymphoma, reflecting a hierarchical organization.
  
  
  METHODS
  Twenty-eight client-owned dogs with previously untreated B-cell lymphoma and 6 healthy dogs.
  
  
  METHODS
  This was a prospective study. Flow cytometry was used to identify lymphoid progenitor cells (LPCs) that coexpressed hematopoietic progenitor antigens CD34, CD117, and CD133, with lymphoid differentiation markers CD21 and/or CD22 in B-cell lymphoma. The polymerase chain reaction for antigen receptor rearrangements was used to analyze clonality and relatedness of tumor populations. A xenograft model with NOD/SCID/IL-2Rγ(-/-) mice was adapted to expand and serially transplant primary canine B-cell lymphoma.
  
  
  RESULTS
  LPCs were expanded in lymph nodes from 28 dogs with B-cell lymphoma compared with 6 healthy dogs (P= .0022). LPCs contained a clonal antigen receptor gene rearrangement identical to that of the bulk of tumor cells. Canine B-cell lymphoma xenografts in recipient mice that maintained LPCs in the tumors were recurrently observed.
  
  
  CONCLUSIONS
  These results suggest the presence of a hierarchy of tumor cells in B-cell lymphoma as has been demonstrated in other cancers. These findings have the potential to impact not only the understanding of lymphoma pathogenesis but also the development of lymphoma therapies by providing novel targets for therapy.
authors.affiliation: Department of Veterinary Clinical Sciences, College of Veterinary Medicine, University of Minnesota, St Paul, MN, USA. itoxx018@umn.edu
authors.forename: D
authors.initials: D
authors.lastname: Ito
authors.forename: M M
authors.initials: MM
authors.lastname: Endicott
authors.forename: C M
authors.initials: CM
authors.lastname: Jubala
authors.forename: K M
authors.initials: KM
authors.lastname: Helm
authors.forename: R C
authors.initials: RC
authors.lastname: Burnett
authors.forename: B D
authors.initials: BD
authors.lastname: Husbands
authors.forename: A
authors.initials: A
authors.lastname: Borgatti
authors.forename: M S
authors.initials: MS
authors.lastname: Henson
authors.forename: K E
authors.initials: KE
authors.lastname: Burgess
authors.forename: J S
authors.initials: JS
authors.lastname: Bell
authors.forename: W C
authors.initials: WC
authors.lastname: Kisseberth
authors.forename: V E
authors.initials: VE
authors.lastname: Valli
authors.forename: G R
authors.initials: GR
authors.lastname: Cutter
authors.forename: A C
authors.initials: AC
authors.lastname: Avery
authors.forename: K A
authors.initials: KA
authors.lastname: Hahn
authors.forename: T D
authors.initials: TD
authors.lastname: O'Brien
authors.forename: J F
authors.initials: JF
authors.lastname: Modiano
mesh_terms: D000071916:AC133 Antigen; D000818:Animals; D015703:Antigens, CD / Q000032:analysis / Q000276:immunology; D018952:Antigens, CD34 / Q000032:analysis / Q000276:immunology; D015331:Cohort Studies; D004195:Disease Models, Animal; D004283:Dog Diseases / Q000276:immunology / Q000473:pathology*; D004285:Dogs; D005260:Female; D005434:Flow Cytometry / Q000662:veterinary; D006023:Glycoproteins / Q000032:analysis / Q000276:immunology; D016130:Immunophenotyping / Q000662:veterinary; D008221:Lymphoid Tissue / Q000166:cytology / Q000276:immunology / Q000473:pathology*; D016393:Lymphoma, B-Cell / Q000276:immunology / Q000473:pathology*; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D016513:Mice, SCID; D014411:Neoplastic Stem Cells / Q000166:cytology / Q000276:immunology / Q000473:pathology*; D010455:Peptides / Q000032:analysis / Q000276:immunology; D011446:Prospective Studies; D019009:Proto-Oncogene Proteins c-kit / Q000032:analysis / Q000276:immunology; D013047:Specific Pathogen-Free Organisms; D018709:Statistics, Nonparametric; D014183:Transplantation, Heterologous / Q000662:veterinary
chemical_list: D000071916:AC133 Antigen; D015703:Antigens, CD; D018952:Antigens, CD34; D006023:Glycoproteins; D010455:Peptides; C000606024:Prom1 protein, mouse; D019009:Proto-Oncogene Proteins c-kit