Molecular pathogenesis of chronic myeloid leukaemia.
The abnormal haemopoietic precursor cells of chronic myeloid leukaemia (CML) carry the cytogenetic abnormality [t(9;22)(q34;q11)]--a reciprocal translocation that results in the expression of a chimaeric protein derived from the fused BCR and ABL genes. This Bcr-Abl protein tyrosine kinase mediates an array of effects on signal transduction pathways affecting cell survival, proliferation, adhesion and genetic stability. The end-result of these abnormal signalling processes is a bi- or triphasic clinical disease. Initially, CML is characterised by the presence of an excess of myeloid progenitor cells and their mature progeny. This chronic phase of CML is followed, either directly or with an intervening 'accelerated phase', by a stage where primitive blast cells predominate (acute transformation). This review discusses the role of Bcr-Abl-mediated signalling events in cellular transformation, genetic instability and disease progression in CML, and describes current developments in CML treatment using a Bcr-Abl inhibitor.
Leukaemia Research Fund Unit, Department of Biomolecular Sciences, University of Manchester Institute of Science and Technology, Sackville St, Manchester, M60 1QD, UK. duncan.smith@renovo.com
Duncan L
DL
Smith
John
J
Burthem
Anthony D
AD
Whetton
D002874:Chromosome Mapping; D002892:Chromosomes, Human, Pair 22; D002899:Chromosomes, Human, Pair 9; D016044:Fusion Proteins, bcr-abl / Q000235:genetics / Q000378:metabolism; D016313:Genes, abl / Q000235:genetics; D006410:Hematopoiesis; D006801:Humans; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000097:blood / Q000235:genetics* / Q000473:pathology*; D008954:Models, Biological; D014178:Translocation, Genetic
D016044:Fusion Proteins, bcr-abl