Development of myelosarcomas from human myelogenous leukemia cells transplanted in athymic mice.

Abstract

Summary Human myelogenous leukemia cells from the Ph 1 + line K562 were transplanted into 1093 nude mice. By incorporation of 5 × 10 6 cells from suspension cultures into fibrin clots, a serially transplantable tumor was obtained and has been maintained for 30 mouse-to-mouse passages during a 2.5 year period. Transplanted mice developed solid, vascularized myelosarcomas containing cells nearly identical with those seen in both the patient and in tissue culture. The growth pattern of the primary myelosarcomas could be divided into three periods. Period 1 was a latent period lasting approximately 5 days after transplantation and characterized by high mitotic activity of the cells in the peripheral area of the transplant and necrosis in the central portion. Period 2, a proliferative period with an exponential increase in tumor size, followed. Rich vascularization developed during this stage. The host reticular cells provided a fiber framework that guided the inward proliferation of leukemia cells while the fibrin in the center of the transplant was absorbed. Period 3, a stable period, followed, during which capillaries were infiltrated by leukemia cells and intratumoral hemorrhagic and ischemic necrotic areas appeared. Thus, the thrombosis was one of the mechanisms precluding the spread of the cells, and a peripheral leukemia or other type of metastatic growth was not observed. The second and subsequent passages were made by taking tissue blocks from the myelosarcomas. Tumor incidence was nearly 100% in most serial passages. The transplanted cells maintained the morphology, the human karyotype including the Ph 1 + chromosome, the translocation 15;17, and the antigenic markers characteristic of the K562 cells in suspension cultures throughout the 30 serial passages. Only 20 to 30% of the myelosarcoma cells were viable in the proliferative period even though the tumors were growing rapidly. The incorporation of [ 3 H]thymidine into these myelosarcomas was essentially identical on a comparative weight basis. The increased total uptake of [ 3 H]thymidine in older tumors was due to an increased tumor mass and, therefore, a greater number of cells undergoing mitosis than in the younger and smaller myelosarcomas. The K562 cell line provides a unique source of cells for sequential studies on the formation of a solid tumor originating from isolated malignant cells. Since the characteristics of the myelosarcoma are maintained for long periods of time, this model could be very useful for therapeutic trials. Any other human tumor-mouse model would have to be characterized by similar sequential studies to provide meaningful information as a bioassay system for therapeutic screening.