The BN acute myelocytic leukemia (BNML) (a rat model for studying human acute myelocytic leukemia (AML))

Abstract

Even if animal models have many properties in common with the human disease, as is the case for the BNML and human AML, they have their limitations with respect to the extrapolation to the clinical situation. This also holds for the BNML; thus, conclusions should only be drawn with great caution. Nevertheless, the studies in the BNML model have added considerably to the understanding of various processes that occur during the development of leukemia, e.g., the interaction of leukemic cells and normal hemopoietic stem cells in relation to the microenvironment. The methodology developed in the BNML model allows the quantification of the relative effectiveness of any given treatment with regard to the antileukemic activity compared with the toxicity for normal host tissues. Furthermore, the cell kinetic studies performed in the BNML as a consequence of timed sequential chemotherapy has been helpful in designing an approach to take advantage of this phenomenon in the treatment of acute leukemia. The comparison of the various treatment modalities, employed for the conditioning prior to bone marrow transplantation, made it possible to determine the relative effectiveness of the various approaches. The fractionation of total body irradiation for conditioning purposes was supposed to have a negligible effect with regard to a reduced antileukemic effect. Detailed studies that were conducted in the BNML model did not confirm this hypothesis indicating that (hyper-)fraction of TBI results in a reduced antileukemic effect. The in vitro purging studies in the BNML aimed at the elimination of residual leukemic cells in autologous bone marrow transplantation contributed to the introduction of this method in clinical practice. However, extended studies in the BNML model also indicated that the contribution of the residual leukemia cell in the patient contributed to a much greater extend to the recurrence of leukemia then did the residual cells in the autologous marrow graft. A major contribution of the BNML was achieved in the study of the area of so-called "minimal residual disease" (MRD). A number of so-far unknown aspects of relapsing leukemia could be identified and studied. A new concept of discriminating locally relapsing leukemia and a delayed occurrence of generalized spreading of leukemia formed the basis for the explanation of the observed heterogeneity in the distribution of leukemic cells during the remission and the subsequent relapse phase. In conclusion, it is obvious that proper comparison of the human disease as well as the counterpart in the animal model requires a detailed knowledge of both.(ABSTRACT TRUNCATED AT 400 WORDS)