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The Effect of Chromosomal Translocations in Acute Leukemias: the LMO2 Paradigm in Transcription and Development I

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The Effect of Chromosomal Translocations in Acute Leukemias: the LMO2 Paradigm in Transcription and Development I [CANCER RESEARCH (SUPPL.) 59, 1794s-1798s, April 1, 1999] The Effect of Chromosomal Translocations in Acute Leukemias: The LMO2 Paradigm in Transcription and Development I Terence H. Rabbitts, 2 Katharina Bucher, Grace Chung, Gerald Grutz, Alan Warren, and Yoshi Yamada Medical Research Council Laboratory of Molecular Biology, Division of Protein and Nucleic Acid Chemistry, Hills Road, Cambridge, CB2 2QH United Kingdom Abstract proto-oncogene from a Burkitt's lymphoma translocation breakpoint t(8;14)(q24;q32) revealed that, while the translocated gene was intact, Two general features have emerged about genes that are activated after there were many mutations in both the noncoding first exon and chromosomal translocations in acute forms of cancer. The protein prod- within the coding region itself (4-11). In T-cell acute leukemias, there ucts of these genes are transcription regulators and are involved in are several different chromosomal translocations found in individual developmental processes, and it seems that the subversion of these normal functions accounts for their role in tumorigenesis. The features of the tumors, and the analysis of these has led to the discovery of many LMO family of genes, which encode LIM-domain proteins involved in different, novel genes that can contribute to T-cell tumorigenesis (1). T-cell acute leukemia through chromosomal translocations, typify these These and many other studies have led to two conclusions: abnormal functions in tumorigenesis. For example, the LMO2 protein is (a) many of the chromosomal translocation-activated oncogenes are involved in the formation of multimeric DNA-binding complexes, which transcription regulators in their normal sites of expression, and it is may vary in composition at different stages of hematopoiesis and function this property that is instrumental in their involvement in tumor etiol- to control differentiation of specific lineages. In T cells, enforced expres- ogy after the chromosomal translocation. This was suggested previ- sion of Lmo2 causes aberrant protein complex formation that primarily ously from the early studies on hematopoietic tumor translocations seems to hinder the T-ceU differentiation program. These observations and later, in addition, from the very large range of changes found in underscore the conclusion that protein-protein interaction (in this case, hematopoietic and mesenchymal tumors (reviewed in Ref. 1); and through the LIM domain) is a key determinant in tumorigenesis. Further- (b) the biological role of many chromosomal translocation-acti- more, the study of chromosomal translocations as naturally occurring mutations has been informative about mechanisms in hematopoiesis as vated genes is normally in developmental processes leading to the well as in tumor etiology. notion that subversion of development may be their crucial biological role in tumorigenesis, perhaps explaining why so few of the chromo- Introduction somal translocation-activated genes were previously identified as on- cogenes from other experimental approaches. The LMO 1 and LMO2 The cytogenetic analysis of tumors, particularly those of hemato- LIM-only proteins are involved in T-cell leukemia because of their poietic origin, have revealed that reciprocal chromosomal transloca- ability to interact with other transcription factors. This enhances the tions are recurring features of these tumors (reviewed in Ref. (1). conclusion that protein-protein interaction is a common component of Furthermore, it has become clear that particular chromosomal trans- oncogene function. locations are consistently found in specific tumor subtypes. Through the cloning of the chromosomal breakpoints and identification of Results and Discussion oncogenes at many different breakpoints, followed by transgenic (2) and homologous recombination knock-in analysis (3), it has become The LMO Family Genes. The LMO family of genes was uncov- clear that these abnormal tumor-associated chromosomes are impor- ered (Fig. 1) by the association of LM01 (previously called RBTN1 or tant in the etiology of tumors. The scientific challenge of the last TTG1) with the chromosomal translocation t(11;14)(p15;ql 1). The decade has been to define the contribution of the genes activated by transcription unit was first observed in a T-cell line (12), and the translocations to the course of tumor development and to ascertain mRNA sequence was obtained from its cDNA sequence (13, 14) and whether any general principles can be discerned about these "trans- shown to encode a protein essentially consisting of two zinc-binding location" genes. LIM domains (15). Using an LMO1 probe, the two related genes There are a variety of chromosomal translocations in leukemias and LM02 and LM03 were isolated (previously called RBTN2 or TTG2 in solid tumors of mesenchymal origin (sarcomas), and two main and RBTN3, respectively; Refs. (16, and 17), of which LM02 was outcomes are apparent (1). One of these is confined to lymphoid found located at the junction of the chromosomal translocation t(11; tumors in which the process of antigen receptor rearrangement (im- 14)(p13;ql 1) in T-ALL 3 (16, 18). The LMO-associated chromosomal munoglobulin and T-cell receptor) occurs and which occasionally translocations seem to have occurred by an error of the usual RAG- aberrantly mediates chromosomal translocation. This type of chromo- mediated variable diversity joining recombinase process inasmuch as somal translocation causes oncogene activation resulting from the sequence analysis of the breakpoints on chromosome 1 lp13 detected new chromosomal environment of the rearranged gene, and, in gen- recombinase signal sequences at the junctions and because the joins eral, this means inappropriate gene expression. In this first category of on chromosome 14 in the TCR~ locus or on chromosome 7 in the chromosomal translocation, the B- and T-cell tumors exemplify many TCR~ locus occur precisely at the end of D-segments (19). consistently occurring features. For instance, the cloning of the CMYC The unique feature of the LMO-derived protein sequences is that they are small proteins comprising two tandem LIM domains. These Received 11/11/98; accepted 2/4/99. zinc-binding finger-like structures have structural similarities to the 1 Presented at the "General Motors Cancer Research Foundation Twentieth Annual DNA-binding GATA fingers (20, 21) but as yet no case of a specific Scientific Conference: Developmental Biology and Cancer," June 9-10, 1998, Bethesda, LIM-DNA interaction has been reported; rather the function of this MD. This work was supported by the Medical Research Council and by Grants from the Leukaemia Research Fund (United Kingdom) and the National Foundation for Cancer domain seems to be restricted to protein-protein interaction (see Research (United States). K.B. is supported by the Roche Foundation; G.G. was "LMO2 Functions by Protein Interaction"). supported by an EMBO Fellowship, and Y. Y. by Kyoto University. 2 To whom requests for reprints should be addressed, at MRC Laboratory of Molecular Biology, Division of Protein and Nucleic Acid Chemistry, Hills Road, Cambridge, CB2 3 The abbreviations used are: T-ALL, T-cell acute lymphocytic leukemia; bHLH, 2QH United Kingdom. basic-helix-loop-helix; DN, double negative; Tall, Tall/Scl. 1794s Downloaded from cancerres.aacrjournals.org on September 28, 2021. © 1999 American Association for Cancer Research. LMO GENES IN LEUKEMIA LMO2 Is a Regulator of Mouse Hematopoiesis. To gain insights into the function of the LMO genes in tumorigenesis, an integrated approach has been adopted to attempt to understand the normal Pluri-potent cell Myeloid function at the biological level as well as the function of LMO proteins and to use this information to explore the function in tumors. Mes od~erm-'~~ lineage As a first step, gene targeting was used to introduce null mutations in Lymphoid mouse Lmo2 gene, which showed that Lmo2 is necessary for yolk sac Self-renewa/j lineage erythropoiesis in mouse embryogenesis (22). Furthermore, the use of embryonic stem cells with null mutations of both alleles of Lmo2 in Lmo2 null defect chimeric mice has shown that adult hematopoiesis, including lympho- poiesis and myelopoiesis, fails completely in the absence of Lmo2 Fig. 2. Lmo2 is necessary for adult hematopoiesis in mice. The tissue contribution of embryonic stem cells with homozygous null mutation of Lmo2 showed that hematopoiesis (23). These data show that Lmo2 must function at early stages of in adult mice is dependent on this gene (23). Thus, the gene product is required for all of hematopoiesis (Fig. 2) either at the level of the pluripotent stem cell the stages of adult hematopoiesis, functioning at least before the bifurcation of myeloid and lymphoid lineages. The function may be restricted to the bone marrow stem cell or even perhaps before this when ventral mesoderm gives rise to these (either at the self-renewal stage or at the proliferative stages that produce committed precursor cells. Remarkably similar results have been shown for progenitors) or in the ventral mesoderm bone marrow precursor cells. another T-cell oncogene, Tall/Scl (herein called Tall; Refs. (24-27). The notion of genes that function in developmental processes is clearly delineated by the Lmo2 gene. LDB1 interact in vivo in T-ALL and in neuroblastoma cell lines (41). LMO2 Functions by Protein Interaction: The Role of the LIM This array of interactions led to the observation that Lmo2 is found in Domain. The concept that oncogenes can interfere with developmen- an oligomeric complex in erythroid cells that involves--in addition to tal processes because they are themselves normally performing this Lmo2--Tall, E47, Ldbl and Gata-I (40). This complex is able to function has been suggested to explain their role in tumor etiology. bind DNA at least in vitro and in reporter assays, with the Lmo2 and The finding that genes that encode proteins such as Lmo2 control Ldbl components seeming to bridge a bipartite DNA-binding com- development of hematopoietic lineages led to clear tests of molecular plex (Fig. 3A). These findings suggest that Lmo2 is part of a tran- function in both normal and tumor contexts.
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