Cytokine-dependent engraftment of human myeloid leukemic cell lines in immunosuppressed nude mice.
To develop a model in which growth factor dependent human acute myeloid leukemia (AML) cells could be reliably engrafted onto murine recipients, the IL-3 or GM-CSF dependent human leukemic cell lines MO7E and TF-1 were engineered by infection with recombinant retroviruses to produce one of these factors. Retrovirally-infected, factor-producing MO7E or TF-1 cells became factor independent in culture while cells infected with a control (neo(r)) retrovirus did not. When these cells were injected intravenously into immunosuppressed Balb/C-nu/nu mice, human CD45+ cells were detected in the marrow of all 30 mice receiving hIL-3 or hGM-CSF-producing cells, but in 0/36 mice injected with uninfected or neo(r) virus-infected MO7E or TF-1 cells. Leukemic cell dissemination in mice injected with factor-producing MO7E cells progressed to cause hind limb paralysis in all animals by 7-12 weeks, and to involve the spleen and peripheral blood in 10/18 and 9/18 mice respectively. Injection of factor-producing TF-1 cells resulted in posterior thoracic tumor masses in all 12 mice by 5-11 weeks, while the spleen and blood were involved in six of those same animals. Southern analysis of retroviral integration sites demonstrated that the polyclonal nature of cells injected into mice was retained in the cells recovered from the same animals. When mice were injected with neo(r) virus-infected MO7E cells followed by 6 micrograms hIL-3 q/2 days i.p. all six mice showed hind limb paralysis and bone marrow involvement with a polyclonal population of MO7E cells by 8-13 weeks post injection. Thus, factor-dependent human AML cell lines will engraft in immunosuppressed, athymic nu/nu mice and disseminate with a pattern resembling human leukemia when provided with a source of the human factor(s) on which their growth is dependent in vitro.
Thacker
J D
JD
Terry Fox Laboratory, British Columbia Cancer Agency, Vancouver, Canada.
Hogge
D E
DE
D000818:Animals; D015139:Blotting, Southern; D004273:DNA, Neoplasm / Q000032:analysis; D006085:Graft Survival; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000096:biosynthesis / Q000502:physiology*; D006801:Humans; D007165:Immunosuppression Therapy; D007377:Interleukin-3 / Q000096:biosynthesis / Q000502:physiology*; D015470:Leukemia, Myeloid, Acute / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D012192:Retroviridae Infections / Q000378:metabolism
D004273:DNA, Neoplasm; D007377:Interleukin-3; D016178:Granulocyte-Macrophage Colony-Stimulating Factor