THE KINETICS AND EXTENT OF ENGRAFTMENT OF CHRONIC MYELOGENOUS LEUKEMIA-CELLS IN NONOBESE DIABETIC SEVERE COMBINED IMMUNODEFICIENCY MICE REFLECT THE PHASE OF THE DONORS DISEASE - AN IN-VIVO MODEL OF CHRONIC MYELOGENOUS LEUKEMIA BIOLOGY/

In vitro studies have provided little consensus on the kinetic abnorma lity underlying the myeloid expansion of chronic myelogenous leukemia (CML). Transplantation of human CML cells into non-obese diabetic mice with severe immunodeficiency disease (NOD/SCID mice) may therefore be a useful model. A CML cell line (BV173) and peripheral blood cells co llected from CML patients in chronic phase (CP), accelerated phase (AP ), or blastic phase (BP) were injected into preirradiated NOQ/SCID mic e. Animals were killed at serial intervals; cell suspensions and/or ti ssue sections from different organs were studied by immunohistochemist ry and/or flow cytometry using antihuman CD45 monoclonal antibodies (M oAbs), and by fluorescence in situ hybridization (FISH) for the BCR-AB L fusion gene. One hour after injection, cells were sequestered in the lungs and liver, but 2 weeks later they were no longer detectable in either site. Similar short-term kinetics were observed using Cr-51-lab eled cells. The first signs of engraftment for BV173, AP, and BE cells were detected in the bone marrow (BM) at 4 weeks. At 8 weeks the medi an percentages of human cells in murine marrow were 4% (range, 1 to 9) for CP, 11% (range, 5 to 36) for AP, 38.5% (range, 18 to 79) for BE, and 54% (range, 31 to 69) for BV173. CP cells progressively infiltrate d BM (21%) and spleen (6%) by 18 to 20 weeks; no animals injected with the cell line or BP cells survived beyond 12 weeks. The rate of incre ase in human cell numbers was higher for BP (7.3%/week) as compared wi th CP (0.9%/week) and AP (0.5%/week). FISH analysis with BCR and ABL p robes showed that same of the human cells engrafting after injection o f CP cells lacked a BCR-ABL gene and were presumably normal. We conclu de that CML cells proliferate in NOD/SCID mice with kinetics that reca pitulate the phase of the donor's disease, thus providing an in vivo m odel of CML biology. (C) 1998 by The American Society of Hematology.