Review

Cytogenetic and Molecular Genetic Aspects of Chronic Myeloid Leukaemia
David J. Barnes, Junia V. Melo

Department of Haematology, Faculty of Medicine, Imperial College of Science, Technology & Medicine, Hammersmith Hospital, London, UK

Address of Corresponding Author

Acta Haematol 2002;108:180-202 (DOI: 10.1159/000065655)

  Key Words

• Chronic myeloid leukaemia
• Cytogenetics
• Molecular genetics
• Oncogenes

  Abstract

Chronic myeloid leukaemia (CML) is caused by the product of the BCR-ABL oncogene, located on the Philadelphia (Ph) chromosome. BCR-ABL is generated as a result of a reciprocal t(9;22) chromosomal translocation. The mechanisms responsible for this illegitimate recombination event remain elusive but are presumed to require a close spatial association of the translocation partners (chromosomes 9 and 22). BCR-ABL fusion transcripts can be detected by a sensitive reverse transcription-polymerase chain reaction (RT-PCR) in the leucocytes of some healthy individuals suggesting that chromosomal translocations may occur frequently in the general population. The presence of BCR-ABL fusion transcripts does not imply that the individual will inevitably develop CML since other conditions must be favourable for expansion of the abnormal clone. Breakpoints in the ABL gene occur within a 5' segment. BCR-ABL fusion transcripts lack ABL exon a1 and consist of BCR exons fused directly to ABL exon a2. The breakpoints in the BCR gene on chromosome 22 are found within three defined regions. Depending on the position of the BCR breakpoint, fusion genes are generated that encode 190-, 210- or 230-kD forms of the Bcr-Abl tyrosine kinase. Since the ABL component of the fusion gene is largely invariant, it follows that variability in disease phenotype may be due to protein sequences encoded by the translocation partner, BCR. Different disease phenotypes are associated with each of the three Bcr-Abl oncoproteins, p190^Bcr-Abl, p210^Bcr-Abl and p230^Bcr-Abl. Mechanisms associated with malignant transformation include altered cellular adhesion, activation of mitogenic signalling pathways, inhibition of apoptosis and proteasomal degradation of physiologically important cellular proteins. CML is subject to an inexorable progression from an 'indolent' chronic phase to a terminal blast crisis. Disease progression is presumed to be associated with the phenomenon of genomic instability.

Copyright © 2002 S. Karger AG, Basel

  Author Contacts

Prof. Junia V. Melo
Department of Haematology - ICSTM, Royal Postgraduate Medical School
Hammersmith Hospital, Du Cane Road
London W12 0NN (UK)
Tel. + 44 20 8383 2167, Fax +44 20 8742 9335, E-Mail j.melo@ic.ac.uk

  Article Information

This review will also appear in: Bain, BJ (ed): Chronic Myeloproliferative Disorders. Cytogenetic and Molecular Genetic Abnormalities. Basel, Karger, 2003.

Number of Figures : 5, Number of Tables : 0, Number of References : 184