Chronic lymphocytic leukemia (CLL) is
IntroductionThe most common leukemia among white adults, B-cell chronic lymphocytic leukemia (CLL), remains incurable and its pathogenesis poorly defined. 1 Currently no system permits differentiation and long-term growth of CLL cells in vitro; therefore, an in vivo animal model that reproducibly supports engraftment and growth of human CLL cells would help elucidate key features of CLL cell biology and lead to better treatments.Previous attempts to engraft human CLL cells into mice have been hampered for 2 reasons. First, xenogeneic recipients were not sufficiently immune deficient to prevent human cell rejection. [2][3][4][5] Although Dü rig et al 5 successfully transferred CLL cells into nonobese diabetes/severe combined immunodeficiency (NOD/SCID) mice, apparently the level of CLL cell growth was not sufficient to correlate kinetics with essential interactions with different cell subpopulations. Second, optimal engraftment and growth may have been impaired by the inability of a murine microenvironment to support CLL cells in vivo. Indeed, in vitro studies suggest at least 3 cell lineages are involved in CLL survival and growth: lymphoid (T cells 6,7 ), myeloid (monocytes and monocyte-derived nurse-like cells 8 ), and mesenchymal ("stromal cells" 9,10 ).To provide a more physiologic microenvironment for CLL cells within highly immune incompetent recipients, we introduced precursors of human hematopoietic and mesenchymal lineages into NOD/Shi-scid,␥c null (NSG) mice, a NOD/SCID-derived strain that lacks the IL-2 family common cytokine receptor gamma chain gene (␥c), rendering animals completely deficient in lymphocytes, including natural killer (NK) cells. We found activated autologous T cells were essential for leukemia cells to successfully engraft, survive, and proliferate in vivo and to recapitulate cardinal features of human CLL cells: kinetics, CD38 expression, and growth in secondary lymphoid tissues. This adoptive transfer model may facilitate the definition of leukemic and nonleukemic elements involved in the interactions and kinetics of CLL cells in patients.
Methods
Patients and samplesThe Institutional Review Board and the Institutional Animal Care and Utilization Committee of the North Shore-LIJ Health System sanctioned these studies. After obtaining informed consent, in accordance with the Submitted December 10, 2010; accepted February 17, 2011. Prepublished online as Blood First Edition paper, March 8, 2011 DOI 10.1182 DOI 10. /blood-2010 An Inside Blood analysis of this article appears at the front of this issue.The online version of this article contains a data supplement.The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked ''advertisement'' in accordance with 18 USC section 1734. For personal use only. on June 7, 2019. by guest www.bloodjournal.org From Declaration of Helsinki, we collected blood from 37 CLL patients for whom clinical information, la...
