Downloaded from genesdev.cshlp.org on September 25, 2021 - Published by Cold Spring Harbor Laboratory Press PERSPECTIVE LMO T-cell translocation oncogenes typify genes activated by chromosomal translocations that alter transcription and developmental processes Terence H. Rabbitts1 Medical Research Council (MRC) Laboratory of Molecular Biology, Division of Protein and Nucleic Acid Chemistry, Cambridge CB2 2QH, UK The cytogenetic analysis of tumors, particularly those of ment (immunoglobulin or T-cell receptor) occurs and oc- hematopoietic origin, has revealed that reciprocal chro- casionally mediates chromosomal translocation. This mosomal translocations are recurring features of these type of translocation causes oncogene activation result- tumors. Further from the initial recognition of the trans- ing from the new chromosomal environment of the re- location t(9;22) (Nowell and Hungerford 1960; Rowley arranged gene. In general, this means inappropriate gene 1973), it has become clear that particular chromosomal expression. The second, and probably the most common translocations are found consistently in specific tumor outcome of chromosomal translocations, is gene fusion subtypes. A principle example of this is the translocation in which exons from a gene on each of the involved chro- t(8;14)(q24;q32.1) invariably found in the human B cell mosomes are linked after the chromosomal transloca- tumor Burkitt’s lymphoma (Manolov and Manolov 1972; tion, resulting in a fusion mRNA and protein. This type Zech et al. 1976). The link with the immunoglobulin of event is found in many cases of hematopoietic tumors H-chain locus on chromosome 14, band q32.1 (Croce et and in the sarcomas. al. 1979; Hobart et al. 1981) and subsequently with the K These general observations posed many questions light-chain locus on chromosome 2, band p12 (Malcolm about chromosomal translocations and how they might et al. 1982), suggested that the immunoglobulin genes influence tumor growth and progression. The diversity might be associated with the translocation breakpoints. of these aberrant chromosomes questioned whether any The cloning of the CMYC proto-oncogene associated general principles might emerge. A particular enigma with the IgH locus from Burkitt’s lymphoma transloca- was the finding of diverse genes at chromosomal break- tion breakpoint t(8;14)(q24;q32) confirmed this. Through points. T-cell acute leukemia (T-ALL) is one notable case the subsequent cloning of the chromosomal breakpoints in point. The disease is clinically rather constant, yet in other tumors and identification of oncogenes at many individual cases contain one of more than a dozen pos- different breakpoints, followed by transgenic (Adams sible chromosomal translocations. The analysis of these and Cory 1991) and homologous recombination knockin has led to the discovery of many different, novel genes analysis (Corral et al. 1996), it has become clear that that can contribute to T-cell tumorigenesis (Rabbitts abnormal tumor-associated chromosomal translocations 1994). are important in the etiology of tumors (for review, see The genes at breakpoints of many major translocations Rabbitts 1994). The scientific challenge of the last de- have now been cloned, and it has been shown that the cade has been to define the contribution of the genes protein products of these genes frequently have promi- activated by translocations to the course of tumor devel- nent features of transcription regulators, for example, opment and to ascertain whether any general principles the DNA-binding homeodomain of HOX11 in T-ALL can be determined about these ‘translocation’ genes. (Dube et al. 1991; Hatano et al. 1991; Kennedy et al. There are two main outcomes of chromosomal trans- 1991; Lu et al. 1991). Thus, a common theme about the locations in human tumors (for review, see Rabbitts genes activated or fused by chromosomal translocations 1994). The first is confined to the lymphoid tumors in is that they encode transcription regulators in their which the process of antigen receptor gene rearrange- 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 1FAX (01223) 412178. etiology following the chromosomal translocation. In GENES & DEVELOPMENT 12:2651–2657 © 1998 by Cold Spring Harbor Laboratory Press ISSN 0890-9369/98 $5.00; www.genesdev.org 2651 Downloaded from genesdev.cshlp.org on September 25, 2021 - Published by Cold Spring Harbor Laboratory Press Rabbitts addition, the biological role of many chromosomal trans- location-activated genes is normally in developmental processes leading to the idea that subversion of develop- ment may be their crucial biological role in tumorigen- esis, perhaps explaining why so few of the chromosomal translocation-activated genes were identified previously as oncogenes by other experimental approaches. This article summarizes a series of observations on the Figure 1. Lmo2 is necessary for adult hematopoiesis in mice. LMO T-cell oncogenes that embody many of the salient The tissue contribution of embryonic stem cells with homozy- features of the chromosomal translocation-activated gous null mutation of Lmo2 showed that hematopoiesis in adult genes. The results also show that the study of these natu- mice is dependent on this gene (Yamada et al. 1998). Thus, the rally occurring mutations have helped in the understand- gene product is required for all stages of adult hematopoiesis, ing of mechanisms in hematopoiesis and act as a para- functioning at least prior to the bifurcation of myeloid and lym- digm, underscoring the conclusion that protein–protein phoid lineages. The function may be restricted to the bone mar- interactions are a key determinant in tumorigenesis and row stem cells (either at the self-renewal stage or at the prolif- in hematopoiesis. erative stages that produce committed progenitors) or in the ventral mesoderm bone marrow precursor cells. The LMO family of T-cell oncogenes pertinent to the cell type involved in initiation of T-cell tumors (see below). The LMO (LIM–only) family of genes (Table 1) was un- The unique feature of the LMO-derived protein se- covered by the association of LMO1 (previously called quences is that they are small proteins comprising two RBTN1 or TTG1) with the chromosomal translocation tandem LIM domains. These zinc-binding finger-like t(11;14)(p15;q11). The transcription unit was first ob- structures have structural similarities to the DNA-bind- served in a T-cell line (Boehm et al. 1988), and the ing GATA fingers (Perez-Alvarado et al. 1994), but as yet mRNA sequence was obtained from its cDNA sequence no case of a direct, specific LIM–DNA interaction has (McGuire et al. 1989; Boehm et al. 1990b) and shown to been reported; rather the function of this domain appears encode a protein essentially consisting of two zinc-bind- to be restricted to protein–protein interaction (see be- ing LIM domains (Boehm et al. 1990a). Using an LMO1 low). probe, the two related genes LMO2 and LMO3 were iso- lated (previously called RBTN2 or TTG2 and RBTN3, respectively) (Boehm et al. 1991; Foroni et al. 1992), of Lmo2 is a regulator of hematopoiesis which LMO2 was found located at the junction of the in normal mouse development chromosomal translocation t(11;14)(p13;q11) in T-ALL To gain insights into the function of the LMO genes in (Boehm et al. 1991; Royer-Pokora et al. 1991). As pro- tumorigenesis, an integrated approach has been adopted posed for other translocations (Finger et al. 1986), the to attempt to understand normal function at the biologi- LMO-associated chromosomal translocations appear to cal and molecular levels of LMO proteins and to utilize have occurred by an error of the RAG-mediated V(D)J this information to explore the function in tumors. As a recombinase process, as sequence analysis of the break- first step, gene targeting was used to introduce null mu- points on chromosome 11p13 detected recombinase sig- tations in the mouse Lmo2 gene, which showed that nal-like sequences at the junctions and because the joins Lmo2 is necessary for yolk sac erythropoiesis in mouse on chromosome 14, in the TCRd locus, or on chromo- embryogenesis (Warren et al. 1994). Furthermore, the use some 7, in the TCRb locus, occur precisely at the end of of ES cells with null mutations of both alleles of Lmo2 in TCR D or J segments (Sanchez-Garcia et al. 1991). This chimeric mice has shown that adult hematopoiesis, in- association with mistakes by V(D)J recombinase seems cluding lymphopoiesis and myelopoiesis, fails com- pletely in the absence of Lmo2 (Yamada et al. 1998). Table 1. The LMO family of genes and T-cell oncogenes These data show that Lmo2 must function during the Chromosome early stages of hematopoiesis at the level of the pluripo- tent stem cell, of the immediate multipotential progeny Gene man mouse Human translocation or even perhaps before this when ventral mesoderm LMO1 11p15 7 t(11;14)(p15;q11) gives rise to these precursors (Fig. 1). A significant simi- LMO2 11p13 2 t(11;14)(p13;q11) larity occurs with results described for another T-cell LMO3 12p12–13 6 N.D. oncogene Tal1/Scl (herein called Tal1) (Porcher et al. 1996; Robb et al. 1996). This gene was discovered be- The LMO gene family (previously called RBTN and TTG genes) cause it is activated in a subset of human T-cell acute has three known members. LMO1 (previously RBTN1/TTG1) leukemias by chromosomal translocations or by pro- was identified first and then LMO2 (previously RBTN2/TTG2) and LMO3 (previously RBTN3). LMO1 and LMO2 are both lo- moter deletions (Begley et al. 1989a,b; Bernard et al. cated on the short arm of chromosome 11 and are both involved 1989; Finger et al. 1989; Chen et al. 1990a,b). The gene in independent chromosomal translocations in human T-ALL.