Genetic rearrangements in leukaemia and lymphoma / J.M. Goldman, D.G. Harnden.

Date:
1986
Catalogue details

Licence: Attribution-NonCommercial 4.0 International (CC BY-NC 4.0)

Credit: Genetic rearrangements in leukaemia and lymphoma / J.M. Goldman, D.G. Harnden. Source: Wellcome Collection.

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    20 GENETIC REARRANGEMENTS Therefore attention must focus, at present, on the RNA retroviruses. Specific types of leukaemia in several species are associated with particular RNA retroviruses, which have very precise target cell specificities. They may be divided broadly into two classes: 1. Those which induce rapid cellular transformation and which, on injection into an appropriate host, will cause leukaemia after a brief latent period; and 2. Those slowly transforming viruses, which do not normally transform cells in culture and which cause leukaemia in the intact animal, only after a prolonged latent period. Rapidly transforming viruses contain transforming sequences (v-onc genes), while slow transforming viruses do not. Most, if not all, normal cells contain regions of the DNA with close sequence homology to these viral one genes. These cellular sequences have been termed proto-oncogenes or c-onc genes. Since the cellular onc-genes contain introns and the v-onc genes do not, it is implied that the v-onc genes have been derived in an evolutionary sense from the cellular sequences by a process involving reverse transcription. The c-onc genes do not themselves have the capacity for cellular transformation. It is clear that activation must occur and also that this may arise in a number of different ways. There are clear examples of activation by gene mutation, gene deletion, introduction of promoting or enhancing sequences, and possibly gene amplification. The c-onc genes are therefore good candidates for cancer genes in the sense described earlier. They are apparently genes controlling vital, normal cellular functions whose mutation or mis regulation are associated with neoplastic progression. This is not the place to go into detail of the nature of one genes, but rather to consider their possible role in human leukaemia. Attention was drawn to the proximity of the one genes to points of chromosome exchange and Table 1.10 gives a list of human one genes, which have been located at specific chromosomal sites - either by in situ hybridization, or by somatic cell genetic techniques involving hybridization of cells containing specific translocations. Some of the localizations are quite precise, while some are, at present, only tentative. It is clear that a number of these one genes are located at or close to the break points of the specific translocations observed in human leukaemias. In particular, c-myc is located at the breakpoint on chromosome 8 in the t(8;14) and the other translocations involved in B-cell lymphomas^. It is of great interest that the secondary break points on chromosomes 14, 2 and 22 are close to the loci coding for the immunoglobulin heavy chain, the к light chain and the X light chains respectively An exactly analogous situation exists in the mouse, where rearrangements involve chromosome 15 and the chromosomes which carry the immunoglobulin genes (Table 1.11 ). The direct involvement of the c-myc gene and the immunoglobulin loci in these exchanges is quite clear from the description of the junction fragments of DNA which contain sequences of both genes®®'®®. The precise mechanisms involved are not yet clear. The breakpoint on chromosome 9 in the t(9;22) translocation in chronic myeloid leukaemia (CML) is close to the location of the c-abl gene; indeed it is J