The mechanism of inhibition of haemopoiesis in acute leukaemia.

One characteristic feature of human acute leukaemia is a depression of normal haemopoiesis which, according to the results of in vitro colony formation, seems to be more severe in acute myeloid leukaemia (AML) than in acute lymphocytic leukaemia (ALL). In our rat model for AML, the transplantable Brown Norway myeloid leukaemia (BNML), near total suppression of haemopoiesis was observed in a relatively early stage of the disease because of the physical disappearance of haemopoietic stem cells (HSC) from the bone marrow, which was only partly compensated by an increased number of HSC in the spleen. The few HSC remaining in the BNML bone marrow in the terminal stage of the disease were mostly out of cycle, in contrast to the HSC in normal rat marrow. Studies with injected labelled leukaemic cells revealed that both BNML and cells of a transplantable lymphatic leukaemia home in the subendosteal region of the femoral bone marrow. Subsequently, ALL cells become randomly distributed over the whole marrow space, while BNML cells remain localized in the subendosteal region. The latter area contains in normal rat marrow a higher proportion of proliferating blast cells than the central area of the marrow, which is reminiscent of the kinetic gradient described in mouse bone marrow by Shackney et al. [22]. These observations support the hypothesis that the depression of normal haemopoiesis in AML is caused by a specific localization and proliferation of AML cells in the subendosteal area, which normally provides the optimal microenvironment for HSC self-replication. In ALL the more severe depression of haemopoiesis occurs in a later stage and is caused by random replacement of HSC as a result of non-specific overgrowth.