Chromosomal Translocations in Leukaemia: Emerging Networks

Abstract

The molecular dissection of the genetic causes of leukaemia has been helped by the relative ease with which leukaemic cells can be subjected to cytogenetic analysis. Almost 40 years ago it was noted that a peculiar small chromosome was a constant feature of chronic myeloid leukaemia (CML) (Nowell and Hungerford, 1960). This so-called Philadelphia chromosome was initially thought to be a partially deleted G-group chromosome. However, it became apparent in the early seventies when the first chromosome banding techniques were developed that the Philadelphia chromosome was a derivative chromosome 22 and the result of a reciprocal translocation between chromosomes 9 and 22 (Rowley, 1973). It still was not known whether this recurring translocation was the result of the malignant transformation process or whether it was indeed the cause of this process. When the breakpoints of the t(9;22)(q34;q11) were analysed at the molecular level in the early 1980s it was shown that they were located in the introns of two genes: the Abelson tryosine kinase gene (ABL) on 9q34 and a gene called break point cluster region (BCR) on 22q11 (Heisterkamp et al., 1983). The breaking and rejoining of the two chromosomes created two chimeric genes: the BCR/ABL chimeric gene on the Philadelphia chromosome (the der(22)) and the ABL/BCR gene on the derivative chromosome 9. These chimeric genes give rise to chimeric or fusion mRNAs which in turn can be translated into fusion proteins (Heisterkamp et al., 1985; Shtivelman et al., 1985). The open reading frame of the 3’ fusion partner is used correctly so that the resulting protein are true chimeras containing at their N-terminus the amino acid sequence of the 5′ gene and in their C-terminal region the amino acid sequence of the 3′ gene. The generation of transgenic mice that expressed the BCR/ABL fusion protein proved that this protein was indeed capable of causing leukaemia (Heisterkamp et al., 1990). Recently, experiments using mice with inducibly BCR/ABL transgenes showed that BCR/ABL is not only required for the initiation of the malignant transformation but also for the maintenance of the transformed state (Huettner et al., 2000).