A novel adoptive transfer model of chronic lymphocytic leukemia suggests a key role for T lymphocytes in the disease

• Published in: Blood Vol. 117; no. 20; pp. 5463 - 5472
• Main Authors: Bagnara, Davide, Kaufman, Matthew S., Calissano, Carlo, Marsilio, Sonia, Patten, Piers E.M., Simone, Rita, Chum, Philip, Yan, Xiao-Jie, Allen, Steven L., Kolitz, Jonathan E., Baskar, Sivasubramanian, Rader, Christoph, Mellstedt, Hakan, Rabbani, Hodjattallah, Lee, Annette, Gregersen, Peter K., Rai, Kanti R., Chiorazzi, Nicholas
• Format: Journal Article
• Language: English
• Published: Washington, DC Elsevier Inc 19.05.2011; Americain Society of Hematology; American Society of Hematology
• Subjects: Adoptive Transfer; ADP-ribosyl Cyclase 1 - blood; Animals; Antigen-Presenting Cells - immunology; Antigen-Presenting Cells - transplantation; B-Lymphocytes - immunology; B-Lymphocytes - pathology; Biological and medical sciences; Cell Proliferation; Cell Survival; Graft vs Host Disease - etiology; Graft vs Host Disease - immunology; Hematologic and hematopoietic diseases; Humans; Interleukin Receptor Common gamma Subunit - deficiency; Interleukin Receptor Common gamma Subunit - genetics; Leukemia, Lymphocytic, Chronic, B-Cell - immunology; Leukemia, Lymphocytic, Chronic, B-Cell - pathology; Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis; Lymphocyte Activation; Lymphocyte Depletion; Lymphoid Neoplasia; Medical sciences; Medicin och hälsovetenskap; Membrane Glycoproteins - blood; Mice; Mice, Inbred NOD; Mice, Knockout; Mice, SCID; Models, Immunological; Neoplasm Transplantation; T-Lymphocytes - immunology; T-Lymphocytes - transplantation; Transplantation, Autologous; Transplantation, Heterologous; Transplantation, Homologous; Tumor Cells, Cultured; Chronic lymphocytic leukemia; Hematology; Lymphoproliferative syndrome; T-Lymphocyte; Malignant hemopathy; Models; Adoptive transfer; Cancer
• ISSN: 0006-4971; 1528-0020; 1528-0020
• DOI: 10.1182/blood-2010-12-324210

Chronic lymphocytic leukemia (CLL) is an incurable adult disease of unknown etiology. Understanding the biology of CLL cells, particularly cell maturation and growth in vivo, has been impeded by lack of a reproducible adoptive transfer model. We report a simple, reproducible system in which primary CLL cells proliferate in nonobese diabetes/severe combined immunodeficiency/γcnull mice under the influence of activated CLL-derived T lymphocytes. By cotransferring autologous T lymphocytes, activated in vivo by alloantigens, the survival and growth of primary CFSE-labeled CLL cells in vivo is achieved and quantified. Using this approach, we have identified key roles for CD4+ T cells in CLL expansion, a direct link between CD38 expression by leukemic B cells and their activation, and support for CLL cells preferentially proliferating in secondary lymphoid tissues. The model should simplify analyzing kinetics of CLL cells in vivo, deciphering involvement of nonleukemic elements and nongenetic factors promoting CLL cell growth, identifying and characterizing potential leukemic stem cells, and permitting preclinical studies of novel therapeutics. Because autologous activated T lymphocytes are 2-edged swords, generating unwanted graph-versus-host and possibly autologous antitumor reactions, the model may also facilitate analyses of T-cell populations involved in immune surveillance relevant to hematopoietic transplantation and tumor cytoxicity.