CHANGING BONE-MARROW MICROENVIRONMENT DURING DEVELOPMENT OF ACUTE MYELOID-LEUKEMIA IN RATS

The Brown Norwegian rat transplanted with promyelocytic leukaemic cell s (BNML) has been used as a model for human acute myeloid leukaemia. W e have previously shown that both the blood supply to the bone marrow and the metabolic rate decrease in relation to the leukaemic developme nt in these rats. Here we have investigated how the development and pr ogression of this leukaemia affect oxygenation, pH and proliferation o f normal and leukaemic cells in vivo. Bone marrow pH was measured by a needle electrode. Nitroimidazol-theophylline (NITP) was used to ident ify hypoxic cells, and eve applied bromodeoxyuridine (BrdUrd) to ident ify DNA replicating cells. The leukaemia progressed slowly until day 2 7 after which a rapid deterioration could be observed leading to sever e changes over the following 5 d. In whole blood there was evidence of progressing metabolic acidosis. In bone marrow the fraction of leukae mic cells increased to > 90% and the pH dropped to about 6.5. The frac tion of NITP+ cells increased to > 80% in bone marrow and to about 40% in blood. The fraction of ErdUrd(+) cells was unchanged in blood. but decreased in bone marrow both for normal cells (from about 20% to 5%) , and far leukaemic cells (from about 45% to 25%), evidently as a resu lt of the severely changed microenvironment. In this study we have dem onstrated in vivo the development of an acidic and hypoxic bone marrow hampering normal haemopoiesis during leukaemic growth. Our data suppo rt the notion of BNML as a valuable tool for studying leukaemogenesis.