CHRONIC MYELOID-LEUKEMIA AS A PARADIGM FOR ONCOGENESIS

Chronic myeloid leukaemia (CML) is a malignant disorder with a long recognised and typical clinicopathological picture, showing an increasingly dedifferentiated and malignant phenotype with disease progression. There is a corresponding evolution of a series of chromosomal events, from the primary (highly specific) abnormality in the early and chronic phases, to the secondary (less specific but non-random) changes in the accelerated phase, and finally to the tertiary (multiple non-specific and random) changes which may be seen in the terminal stages. The primary chromosomal stage is associated with the dysregulation of a specific cellular oncogene, and this change has been demonstrated, both in vitro and in vivo, to be essential for the development of the malignant phenotype. Dysregulation of other oncogenes likely occurs with the acquisition of additional non-random (secondary) chromosomal abnormalities which often accumulate in the accelerated phase of the disease. CML constitutes a model for the evolution of stages of oncological development which is readily accessible for use in man and in experimental systems, and which allows the clinical, biological and genetic stages to be separated for detailed study. The chromosomal and molecular abnormalities are used as markers of disease for diagnosis, prognosis and monitoring of therapy. Better understanding of the cellular mechanisms of disordered proliferation and differentation in CML should ultimately lead to more specific and effective therapeutic strategies to replace the current somewhat unsatisfactory modalities and assist in developing new approaches to the management of malignant disease in general.