LMO T-cell translocation oncogenes typify genes activated by chromosomal translocations that alter transcription and developmental processes.

The cytogenetic analysis of tumors, particularly those of hematopoietic origin, has revealed that reciprocal chromosomal translocations are recurring features of these tumors. Further from the initial recognition of the translocation t(9;22) (Nowell and Hungerford 1960; Rowley 1973), it has become clear that particular chromosomal translocations are found consistently in specific tumor subtypes. A principle example of this is the translocation t(8;14)(q24;q32.1) invariably found in the human B cell tumor Burkitt’s lymphoma (Manolov and Manolov 1972; Zech et al. 1976). The link with the immunoglobulin H-chain locus on chromosome 14, band q32.1 (Croce et al. 1979; Hobart et al. 1981) and subsequently with the K light-chain locus on chromosome 2, band p12 (Malcolm et al. 1982), suggested that the immunoglobulin genes might be associated with the translocation breakpoints. The cloning of the CMYC proto-oncogene associated with the IgH locus from Burkitt’s lymphoma translocation breakpoint t(8;14)(q24;q32) confirmed this. Through the subsequent cloning of the chromosomal breakpoints in other tumors and identification of oncogenes at many different breakpoints, followed by transgenic (Adams and Cory 1991) and homologous recombination knockin analysis (Corral et al. 1996), it has become clear that abnormal tumor-associated chromosomal translocations are important in the etiology of tumors (for review, see Rabbitts 1994). The scientific challenge of the last decade has been to define the contribution of the genes activated by translocations to the course of tumor development and to ascertain whether any general principles can be determined about these ‘translocation’ genes. There are two main outcomes of chromosomal translocations in human tumors (for review, see Rabbitts 1994). The first is confined to the lymphoid tumors in which the process of antigen receptor gene rearrangement (immunoglobulin or T-cell receptor) occurs and occasionally mediates chromosomal translocation. This type of translocation causes oncogene activation resulting from the new chromosomal environment of the rearranged gene. In general, this means inappropriate gene expression. The second, and probably the most common outcome of chromosomal translocations, is gene fusion in which exons from a gene on each of the involved chromosomes are linked after the chromosomal translocation, resulting in a fusion mRNA and protein. This type of event is found in many cases of hematopoietic tumors and in the sarcomas. These general observations posed many questions about chromosomal translocations and how they might influence tumor growth and progression. The diversity of these aberrant chromosomes questioned whether any general principles might emerge. A particular enigma was the finding of diverse genes at chromosomal breakpoints. T-cell acute leukemia (T-ALL) is one notable case in point. The disease is clinically rather constant, yet individual cases contain one of more than a dozen possible chromosomal translocations. The analysis of these has led to the discovery of many different, novel genes that can contribute to T-cell tumorigenesis (Rabbitts 1994). The genes at breakpoints of many major translocations have now been cloned, and it has been shown that the protein products of these genes frequently have prominent features of transcription regulators, for example, the DNA-binding homeodomain of HOX11 in T-ALL (Dube et al. 1991; Hatano et al. 1991; Kennedy et al. 1991; Lu et al. 1991). Thus, a common theme about the genes activated or fused by chromosomal translocations is that they encode transcription regulators in their normal sites of expression (Cleary 1991; Rabbitts 1991; Look 1997). Furthermore, it appears to be this property that can be instrumental in their involvement in tumor etiology following the chromosomal translocation. In FAX (01223) 412178.