• Open Access

A Tumor-Related Lymphoid Progenitor Population Supports Hierarchical Tumor Organization in Canine B-Cell Lymphoma

Authors

  • D. Ito,

    1. Department of Veterinary Clinical Sciences, College of Veterinary Medicine, University of Minnesota, St Paul, MN
    2. Masonic Cancer Center, University of Minnesota, Minneapolis, MN
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  • M.M. Endicott,

    1. Gulf Coast Veterinary Oncology, Houston, TX
    2. Endicott is presently affiliated with the Southern Arizona Veterinary Specialty Emergency and Referral, Tucson, AZ
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  • C.M. Jubala,

    1. Integrated Department of Immunology, School of Medicine, University of Colorado, Denver, CO
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  • K.M. Helm,

    1. University of Colorado Cancer Center, Aurora, CO
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  • R.C. Burnett,

    1. Department of Microbiology, Immunology, and Pathology, Colorado State University College of Veterinary Medicine and Biomedical Sciences, Fort Collins, CO
    2. Animal Cancer Center, Colorado State University College of Veterinary Medicine and Biomedical Sciences, Fort Collins, CO
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  • B.D. Husbands,

    1. Department of Veterinary Clinical Sciences, College of Veterinary Medicine, University of Minnesota, St Paul, MN
    2. Masonic Cancer Center, University of Minnesota, Minneapolis, MN
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  • A. Borgatti,

    1. Department of Veterinary Clinical Sciences, College of Veterinary Medicine, University of Minnesota, St Paul, MN
    2. Masonic Cancer Center, University of Minnesota, Minneapolis, MN
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  • M.S. Henson,

    1. Department of Veterinary Clinical Sciences, College of Veterinary Medicine, University of Minnesota, St Paul, MN
    2. Masonic Cancer Center, University of Minnesota, Minneapolis, MN
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  • K.E. Burgess,

    1. Department of Clinical Sciences, Tufts Cummings School of Veterinary Medicine, North Grafton, MA
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  • J.S. Bell,

    1. Department of Clinical Sciences, Tufts Cummings School of Veterinary Medicine, North Grafton, MA
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  • W.C. Kisseberth,

    1. Department of Veterinary Clinical Sciences, College of Veterinary Medicine, The Ohio State University, Columbus, OH
    2. Comprehensive Cancer Center and Solove Research Institute, The Ohio State University, Columbus OH
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  • V.E. Valli,

    1. Department of Pathobiology, College of Veterinary Medicine, University of Illinois, Urbana, IL
    2. Valli is presently affiliated with the VDx Veterinary Diagnostics, Davis, CA
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  • G.R. Cutter,

    1. Department of Biostatistics, University of Alabama, Birmingham, AL
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  • A.C. Avery,

    1. Department of Microbiology, Immunology, and Pathology, Colorado State University College of Veterinary Medicine and Biomedical Sciences, Fort Collins, CO
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  • K.A. Hahn,

    1. Gulf Coast Veterinary Oncology, Houston, TX
    2. Hahn is presently affiliated with the Hill's Pet Nutrition Inc, Topeka, KS
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  • T.D. O'Brien,

    1. Masonic Cancer Center, University of Minnesota, Minneapolis, MN
    2. Department of Veterinary Population Medicine, College of Veterinary Medicine, University of Minnesota, St Paul, MN
    3. Stem Cell Institute, University of Minnesota, Minneapolis, MN
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  • J.F. Modiano

    1. Department of Veterinary Clinical Sciences, College of Veterinary Medicine, University of Minnesota, St Paul, MN
    2. Masonic Cancer Center, University of Minnesota, Minneapolis, MN
    3. Integrated Department of Immunology, School of Medicine, University of Colorado, Denver, CO
    4. University of Colorado Cancer Center, Aurora, CO
    5. Stem Cell Institute, University of Minnesota, Minneapolis, MN
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  • The main part of this work was performed at the Masonic Cancer Center, University of Minnesota, Minneapolis, MN. A part of the study was presented at AACR 100th Annual Meeting, Washington, DC, April 2010.

Corresponding author: Daisuke Ito, DVM, PhD, Masonic Cancer Center, University of Minnesota, MCRB 530, 425 East River Road, Minneapolis, MN 55455; e-mail: itoxx018@umn.edu.

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.

Hypothesis/Objectives: Tumor cells with a progenitor phenotype exist in B-cell lymphoma, reflecting a hierarchical organization.

Animals: 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 and Clinical Importance: 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.

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