title: The molecular biology of chronic myeloid leukaemia.
abstract: Chronic myeloid leukaemia (CML) is characterized cytogenetically by a t(9;22)(q34;ql1) reciprocal translocation which gives origin to a hybrid BCR-ABL gene, encoding a p2lO(BCR-ABL) fusion protein with elevated tyrosine kinase activity and transforming abilities. The t(9;22) was suggested to be associated with genomic imprinting of centromeric regions of chromosomes 9 and 22, but the genes directly affected by the translocation, ABL and BCR, were shown not to be imprinted. For most diagnostic and research purposes the BCR-ABL gene can be efficiently identified by reverse-transcription and polymerase chain reaction (RT/PCR) amplification of its fusion transcripts, which can be quantified by competitive PCR and similar assays for assessment of residual disease in the follow-up of therapy. In the great majority of CML patients the BCR-ABL transcripts exhibit a b2a2 and/or a b3a2 junction; in rare cases, the only detectable BCR-ABL transcripts have unusual junctions, such as b2a3, b3a3, e1a2 or e6a2. There is a recent suggestion that the BCR-ABL gene may not be always 'functional', since extremely low levels of BCR-ABL transcripts can be found in leucocytes from normal individuals and, conversely, it appears that no BCR-ABL transcription can be detected in a proportion of Ph-positive haematopoietic progenitors from some CML patients. The role, if any, of the reciprocal ABL-BCR hybrid gene in CML is unknown. Although its mRNA message is in frame, no ABL-BCR fusion protein has yet been identified in CML patients. The blast crisis of CML has been variably associated with abnormalities of proto-oncogenes, such as RAS and MYC, or of tumour suppressor genes, in particular RB, p53 and p16, or with the generation of chimeric transcription factors, as in the AML1-EVI1 gene fusion. It is likely, therefore, that multiple and alternative molecular defects, as opposed to a single universal mechanism, underlie the acute transformation of the disease.
authors.affiliation: Department of Haematology, Royal Postgraduate Medical School, London, UK.
authors.forename: J V
authors.initials: JV
authors.lastname: Melo
mesh_terms: D001752:Blast Crisis / Q000235:genetics / Q000473:pathology; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D002892:Chromosomes, Human, Pair 22 / Q000235:genetics / Q000648:ultrastructure; D002899:Chromosomes, Human, Pair 9 / Q000235:genetics / Q000648:ultrastructure; D002999:Clone Cells / Q000473:pathology; D005091:Exons / Q000235:genetics; D016044:Fusion Proteins, bcr-abl / Q000235:genetics* / Q000502:physiology; D015973:Gene Expression Regulation, Leukemic; D016313:Genes, abl; D018392:Genomic Imprinting; D006801:Humans; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D009363:Neoplasm Proteins / Q000235:genetics* / Q000502:physiology; D009857:Oncogenes; D010677:Philadelphia Chromosome
chemical_list: D009363:Neoplasm Proteins; D016044:Fusion Proteins, bcr-abl