© The Author 2008. Published by Oxford University Press.
Modeling Chromosomal Translocations Using Conditional Alleles to Recapitulate Initiating Events in Human Leukemias
Affiliation of authors: MRC Laboratory of Molecular Biology, Cambridge, UK
Correspondence to: Terence H. Rabbitts, Leeds Institute of Molecular Medicine, Section of Experimental Therapeutics, WT Brenner Bldg, St James’s University Hospital, Leeds, LS9 7TF, UK (e-mail: thr{at}leeds.ac.uk).
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ABSTRACT |
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 TopNotes Abstract IntroductionMouse Models of Chromosomal...MLL Translocation Mimics: Knock...MLL Translocation Mimics:...MLL Translocation Mimics:...The Mll-AF4 Protein Causes...ConclusionsFundingReferences |
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Recurrent reciprocal chromosomal translocations are present in more than 50% of leukemias. A deeper understanding of how they affect cancer initiation is essential for evaluating the origins of cancer and the potential for therapy based on the translocation products. Mouse models of chromosomal translocations are required for this. Here we summarize three methodologies developed in our laboratory to model chromosomal translocations (knock-in, translocator, and invertor methods). We have used these models to study leukemias caused by fusions of the mixed lineage leukemia (MLL) gene and the Ews-ERG fusion gene to evaluate oncogenicity and elucidate some general principles about translocation products. We show that MLL fusions have the capacity to cause hematopoietic tumors only if expressed in permissive cells and that the Mll-Enl fusion can cause lineage reassignment if the chromosomal translocation occurs in lineage noncommitted progenitors. The leukemia-initiating cells generated by Mll fusions or by Ews-ERG fusion can be committed cells within the hematopoietic pathway. Our translocation mimic models are applicable to any human reciprocal chromosomal translocation.
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INTRODUCTION |
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TopNotesAbstractIntroductionMouse Models of Chromosomal...MLL Translocation Mimics: Knock...MLL Translocation Mimics:...MLL Translocation Mimics:...The Mll-AF4 Protein Causes...ConclusionsFundingReferences |
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Consistent chromosomal translocations are associated with remarkable specificity in distinct tumor subtypes (1) and can be considered primary events in the initiation of the tumorigenic processes. They are present in more than 50% of all hematological malignancies and many have also been identified in mesenchymal (ie, sarcomas) tumors and some in epithelial tumors (eg, prostate cancer) (2). Since the first reciprocal translocations were reported in 1960–70s (1–4), abundant studies at cytogenetic and molecular level have been carried out to identify the involved genes. The cloning of the translocation breakpoints revealed that the main outcomes of the interchromosomal rearrangements are proto-oncogene activation by juxtaposition to T- or B-cell receptor genes or the creation of fusion genes encoding a chimeric oncogenic protein. The characterization of the chromosomal translocation products, in the acute cancers, showed that they tend to be transcription and developmental regulators, altering the transcription balance and the control of the fate of the affected cell, which led to the chromosomal translocation-master gene model (5).
The study of these cytogenetic changes has had a major impact on the diagnosis, prognosis, and even choice and development of better therapies for the patients, as shown by the improvement in treatment of chronic myeloid leukemia patients with the kinase inhibitor Imatinib (STI571/Gleevec) that targets the enhanced ABL kinase of the BCR-ABL fusion protein (6). However, there remain rather few successes based on the molecular pathology of tumors, and improved technologies and preclinical mouse models are needed to facilitate new developments.
Mouse models for human cancer are, therefore, of crucial importance not only to understand the genetic factors underlying the disease but also for utilizing as a basis for developing new therapeutic strategies. Early work on mouse models made major developments in understanding for cancer (7), and these models are being superceded by compound conditional gene knock-ins and transgenics that permit mimicking of specific aspects of human cancer. Advances in embryonic stem (ES) cell technology and chromosomal engineering have allowed the precise manipulation of the genes involved in translocations, not only to reproduce activated oncogenes but also to create fusion genes.
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Mouse Models of Chromosomal Translocations Using Homologous Recombination |
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TopNotesAbstractIntroductionMouse Models of Chromosomal...MLL Translocation Mimics: Knock...MLL Translocation Mimics:...MLL Translocation Mimics:...The Mll-AF4 Protein Causes...ConclusionsFundingReferences |
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This paper reviews our work to develop a platform of technologies for mimicking human cancer–specific chromosomal translocations in mice. In our laboratory, three different technologies have been developed for making translocation mimics, namely, knock-in, translocator, and invertor methods (see Figure 1). These technologies are based on gene targeting by homologous recombination in ES cells, which offers the advantage that the specific single genetic changes can be made and transmitted through the germline of mice (8).
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Our first approach used was a method that has become known as the knock-in method and which was exemplified 10 years ago by fusing the human AF9 gene into the mouse Mll gene to reproduce the Mll-AF9 fusion (9) (Figure 1, A). This technology showed that the Mll-Af9 fusion causes leukemias of the myeloid lineage (9,10). However, knock-ins lack cell specificity because the targeted allele should be expressed in all cells in which the promoter of the targeted allele is active and can result in embryonic lethality for some translocations whose products interfere with normal mouse prenatal development, including our finding with Mll-AF4 (see below) (11–13). To circumvent these limitations, we developed conditional systems allowing the controlled expression of translocation alleles in different cell types and at different cellular differentiation stages (pluripotent stem cells, semicommitted progenitors, or committed cells).
A conditional mouse model was developed based on the ability of Cre recombinase to mediate interchromosomal translocations (14,15). This method was designated the translocator model (16,17). In this technology, loxP sites are introduced, by homologous recombination, into the appropriate introns of the two genes between which a translocation is desired (Figure 1, B), and Cre expression in mice is used to induce the translocation. As this occurs at low frequency in mice (F. C. Cano, AF & T. H. Rabbitts, unpublished data), the cancers that arise are truly of single-cell origin and the cancer-initiating cell is thereby defined by the cell in which the recombinase is expressed. The translocator model is the ideal method to reproduce de novo, the reciprocal translocations found in human cancers, as both derivative chromosomes that result from the chromosomal rearrangement are generated somatically after Cre-loxP recombination (Figure 1, B). Although, this translocator approach can in principle be applied to recapitulate any human reciprocal translocation, the strategy requires that the genes involved have the same transcription orientation with respect to the centromere in mouse chromosomes. If they do not, any translocation that does occur will do so with the resultant dicentric and acentric derivative chromosomes in a nonviable cell.
A conditional model is required in those cases where the translocator method cannot be used. One approach is the loxP-STOP method (13), in which transcription of a knock-in allele is inhibited by polyA transcription stop site flanked (floxed) by loxP sites to allow Cre-dependent deletion of the transcription stop and thereby activating transcription of the knock-in segment. However, we have found that in some cases, such as Mll-AF4 (see below), there is sufficient transcription read-through of the polyA site that sufficient fusion protein is made to manifest function. In view of this, we developed a fully conditional knock-in method designated the invertor method (18,19) (Figure 1, C). The invertor technology is based on knocking-in of a floxed cDNA cassette into an appropriate intron of a target gene but in the opposite orientation for transcription and splicing. Expression of Cre under a chosen promoter will induce the inversion of the floxed cassette and allow the formation of the fusion gene in a cell-specific manner recapitulating the translocation associated with human leukemia.
Thus, these mouse models and their inducible versions, for instance, those in which the Cre expression can be switched on or off by inducers or repressors such as doxycycline (20) or tamoxifen (21), can be applied to mimic a wide range of human diseases. We have used them to reproduce chromosomal translocations involving the mixed lineage leukemia (MLL) gene (9,16,17,22) and the EWS gene in leukemogenesis (18).
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MLL Translocation Mimics: Knock-in Genes |
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TopNotesAbstractIntroductionMouse Models of Chromosomal...MLL Translocation Mimics: Knock...MLL Translocation Mimics:...MLL Translocation Mimics:...The Mll-AF4 Protein Causes...ConclusionsFundingReferences |
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Of more than 200 fusion genes so far described (2), the chromosomal fusions involving the MLL gene from human chromosome 11, band q23, are the most frequently found in different chromosomal translocations. The MLL gene is highly promiscuous, having more than 60 fusion partners (23,24), and MLL gene fusions contribute
We applied the mouse translocation mimic technologies outlined above to gain insights into a possible instructive role of MLL fusion proteins in leukemia tropism by recapitulating the most frequent MLL chromosomal translocations (MLL-AF4, AF9, and ENL) responsible for more than 60% of leukemias involving MLL gene (see Table 1 for summary of outcome of mouse models). Therefore, an evaluation of their oncogenicity in various cellular contexts should shed light on important issues regarding tumor tropism. MLL-AF9 translocations, resulting from t(9;11), are mainly found in acute myeloid leukemia (AML), and this gene fusion was the first to be reproduced using a knock-in method where a human AF9 cDNA was inserted in the mouse Mll allele (9,10). Chimeric and heterozygous mice carrying the gene fusion developed leukemias beginning at 
6 months and were almost exclusively AMLs. There was also detectable proliferation of myeloid cells in bone marrow by as little as 6 days after birth. It seems likely that the early accumulation of myeloid precursors gives them a greater chance of acquiring secondary mutations that cooperate in the appearance of overt cancer.
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The knock-in model mimicked well the acute leukemia diagnosed in patients with the t(9;11)(p22;q23) and, therefore, provided a suitable mouse model for MLL-AF9 translocation. The knock-in approach allowed further studies by fusing a segment comprising either a short-peptide tag or the lacZ gene (encoding beta-galactosidase, βgal) at the same place in Mll where AF9 had been fused (exon 10) (10). The surprising outcome of these experiments was that we observed leukemias (AML) in the mice expressing Mll-βgal fusion but not those simply with a truncated Mll protein (ie, those with the peptide tag added). As beta-galactosidase had not been previously reported to be oncogenic and because fusing beta-galactosidase with Mll exon 3 by knock-in did not cause tumors (9), we proposed that the Mll-βgal protein was present as a dimer of dimers (via the beta-galactosidase tetrameric interaction) and, therefore, that dimerization was necessary for MLL fusion–mediated oncogenecity (25). Coupled with our subsequent data with the MLL translocator model, we propose that the oncogenic transformation of MLL requires dimer formation, and lineage specification requires specific fusion partners. The "minor" fusion partners probably have no lineage specification property and merely default into myeloid leukemogenesis.
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MLL Translocation Mimics: Translocators |
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TopNotesAbstractIntroductionMouse Models of Chromosomal...MLL Translocation Mimics: Knock...MLL Translocation Mimics:...MLL Translocation Mimics:...The Mll-AF4 Protein Causes...ConclusionsFundingReferences |
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To overcome restrictions imposed by the knock-in approach, we developed a system for de novo translocation production designated translocator (16). Mice were created with the loxP recombination sites introduced into Mll intron 10 (16), Af9 intron 9 (16), and Enl intron 1 (17) and mated with each other and with Cre-expressing lines. In one set of experiments, the promoter chosen to drive Cre recombinase expression was Lmo2, which has characteristic expression in pluripotent stem cells and multipotent myeloid progenitor (26). With this system, only myeloid neoplasias occurred when either Mll-Enl or Mll-Af9 translocations were initiated in hematopoietic stem cells and multipotent myeloid progenitors (27).
In a separate analysis, the Lck promoter was used to control Cre expression [expression being within the T-cell lineage and its progenitors (28,29)] and produced a different outcome. No tumors appeared in the Mll-Af9 translocator model even though translocations could be found in the T cells and fusion messenger RNA could be detected (27). Thus, Mll-Af9 fusion requires the correct cellular context to be oncogenic, and it can be inferred that MLL translocations are not necessarily oncogenic in any hematopoietic cell type. The translocator technology was also used to reproduce the MLL-ENL reciprocal translocation, t(11;19), associated with both myeloid and lymphoid human leukemias (Table 1). Unlike Mll-Af9 translocator mice, Mll-Enl translocators using Lck-Cre presented with hematological malignancies in either the myeloid lineage or the T-cell lineage (25). This mirrors the situation found in patients with leukemias carrying the MLL-ENL fusion. Because the Lck-Cre transgene has no activity in any cell of the myeloid lineage (29), the occurrence of the myeloid lineage tumors in these mice must have come from cells within the T-cell differentiation compartment. This was confirmed by analyzing the status of the T-cell receptor genes, which were found to have undergone Rag-mediated V-D-J joining characteristic of lymphoid lineage development (unlike myeloid tumors from the translocators using Lmo2-Cre). Thus, we conclude that the myeloid tumors caused by the Mll-Enl translocation mediated by the Lck-Cre transgene are due to lineage reassignment from T-lymphoid to myeloid lineages (see Figure 2).
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These data suggest that we can separate the lineage-determining and transformation aspects of MLL fusion–mediated cancer and show that the MLL-ENL fusion protein plays an instructive role in lineage determination of leukemia (Figure 2). The current model is that if an Mll-Enl translocator mouse has a translocation in a permissive T-cell progenitor at a noncommitted stage of differentiation, this would allow lineage reassignment of the developmental pathway directly in response to the Mll-Enl fusion. However, if the translocation event happens in a more differentiated T cell that has moved sufficiently far down the developmental pathway that it has no further developmental options, the leukemia that arises will be of the T-cell lineage. Finally, the Mll-Enl translocation–associated leukemia-initiating cells can appear from within lineage-committed cells and are not restricted to pluripotent hematopoietic stem cells.
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MLL Translocation Mimics: Conditional Invertor Alleles |
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TopNotesAbstractIntroductionMouse Models of Chromosomal...MLL Translocation Mimics: Knock...MLL Translocation Mimics:...MLL Translocation Mimics:...The Mll-AF4 Protein Causes...ConclusionsFundingReferences |
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The translocator model is the ideal recapitulation of the human chromosomal translocation and should be applicable to a range of human translocations. As discussed above, the success with this system depends on the compatibility of the transcription orientation of the two genes on the mouse chromosomes. For those cases where this is not the case, we have developed a different conditional method called invertor mice (18). This method was initially applied to the EWS-ERG fusion gene commonly found in Ewing's sarcoma using Rag1-Cre in the mouse model (29). The rationale was that, while EWS fusions predominate in the Ewing's family of tumors, EWS and the related FUS-fusions are also found in leukemias (30,31). Furthermore, the prevailing dogma was that EWS fusions are activated in primitive stem cells of mesenchymal or hematopoietic lineages. Our results with the Ews-ERG invertor showed that mature T-cell lymphomas arise when the activation of the inverted fusion is mediated by Rag1-Cre, a gene active in both T- and B-cell progenitors. Therefore, like the findings with Mll translocators, we conclude that the tumor-initiating cells for the Ews-ERG–dependent lymphomas are committed cells of the T-cell lineage and not multipotent progenitors (19).
The modeling of MLL-AF4 fusion proved problematic due to the inability to use the translocator model. The MLL-AF4 fusion in infants and children, that results from the t(4;11) translocation, is associated exclusively with B-cell tumors (with an immature B-cell phenotype) and is the most frequent MLL gene fusion in childhood leukemia (24). Further, the fusion is a poor prognostic marker, especially in children more than 1 year of age (32). An Mll-AF4 invertor model was made, as shown in Figure 3, A, knocking-in the AF4 invertor cassette in Mll intron 10 (22). The conditional inversion of AF4 was achieved by mating the invertor mice with those expressing Cre recombinase under the control of the Rag1 or Lck promoters to determine if lymphoid tumors could arise (a control was made using the B-cell–specific CD19 promoter). These lines of mice all developed B-cell tumors with long latency. However, the phenotypes of the tumors were not the immature pro–B-cell leukemias characteristic of the MLL-AF4 childhood leukemia but rather were mature diffuse large B-cell lymphomas (these tumors were very aggressive and transplantable in nude mice) (22). In the case of the CD19-Cre mice, this is not too surprising as the Cre expression is limited to B cells, but for the Rag1-Cre mice, in which Cre is expressed in progenitors of both B and T cells, or T cells expressing Lck-Cre mice, the mature B-cell phenotype was a puzzle suggesting that the pro–B-cell tumors may require specific second mutational events. Nonetheless, the consistent finding of B-cell tumors in the Mll-AF4 invertor mice expressing either Cre from Rag1-Cre or Lck-Cre alleles suggests that the fusion protein has an instructive role in this setting stimulating differentiation into B cells. Also the Mll-AF4 fusion, as Mll-Enl, can be oncogenic in cells, which have at least undergone some degree of lineage commitment (the CD19-Cre invertors), and does not have to be in pluripotent stem cells.
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5' orientation with respect to the endogenous Mll gene. When Cre recombinase was expressed under the Lmo2 promoter, it recognizes the loxP sites (depicted as yellow triangles) and inverts the cassette to create the correct orientation for the AF4 cDNA segment (ie, 5' |
The Mll-AF4 Protein Causes Embryonic Lethality |
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TopNotesAbstractIntroductionMouse Models of Chromosomal...MLL Translocation Mimics: Knock...MLL Translocation Mimics:...MLL Translocation Mimics:...The Mll-AF4 Protein Causes...ConclusionsFundingReferences |
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One curious finding was that our form of the Mll-AF4 fusion protein causes embryo death in mice, unlike that described elsewhere (33). Our initial knock-in of human AF4 cDNA into the Mll exon 10 and a conditional knock-in form (Mll-AF4 loxP-stop) failed to yield chimeric mice because of embryonic lethality (22). Using the Mll-AF4 loxP-stop strategy, it is likely that a minimal read-through of the transcription stop occurred, producing sufficient Mll-AF4 product to invoke lethality.
As a means to develop a system allowing us to examine the cause of the embryonic lethality, mice carrying the Mll-AF4 invertor cassette (depicted in Figure 3, A) were crossed with Lmo2-Cre mice but even that failed to give birth to viable pups of the Mll-AF4; Lmo2-Cre mutant genotype. In some cases, the chimeric embryos survived until embryonic day E12.5, but there were obvious differences in size and color between embryos carrying both knock-in alleles (Mll-AF4 and Lmo2-Cre) and the heterozygous or wild-type ones (Figure 3, B). Tissue sections of invertor embryos showed very few red cells in the embryo body and yolk sac and a considerable retardation in fetal liver development (M. L. Lobato, R. Pannell, T. H. Rabbitts, unpublished data). This effect is dependent on the Mll-AF4 fusion as it only occurs in Mll-AF4; Lmo2-Cre embryos. The Lmo2 gene is expressed early in mouse embryogenesis (around E7.5) and essential for embryonic primitive and definitive hematopoiesis (26,34). Therefore, the activation of Mll-AF4 in Lmo2-Cre invertors should occur from about E7.5 onwards and certainly in the progenitors of primitive hematopoiesis. The impairment of primitive and definitive erythropoiesis may be sufficient to eventually sacrifice the embryos as the lack of red cells has been attributed to the cause of death for Lmo2 null embryos (26). Because these experiments use chimeric embryos, Mll-AF4 expression would not be in all erythroid progenitors, but the eventual combined effect of Mll-AF4 expression in cells of the second wave of erythropoiesis could prove fatal in embryos surviving beyond the primitive erythropoiesis stage. These data suggest that the MLL-AF4 fusion protein has a dominant effect on hematopoiesis, specifically by impeding erythroid development.
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Conclusions |
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TopNotesAbstractIntroductionMouse Models of Chromosomal...MLL Translocation Mimics: Knock...MLL Translocation Mimics:...MLL Translocation Mimics:...The Mll-AF4 Protein Causes...ConclusionsFundingReferences |
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Mouse models have been described for the generation of chromosomal translocations as primary genetic changes using conditional alleles activated at predetermined stages of hematopoiesis. Our studies of these using Mll fusions or the Ews-ERG fusion showed that 1) protein fusions are not necessarily oncogenic in any hematopoietic cell, 2) the late onset of overt leukemia in most cases suggests the necessity of secondary additional mutations, 3) some fusions do not need to occur in pluripotent stem cells to cause leukemia, 4) translocation products can function in committed cells as long as these are permissive to generate a tumor with that fusion, and 5) some Mll translocation products can be responsible for lineage reassignment of noncommitted lymphoid cells.
These chromosomal translocation mimics have provided valuable information about the role of consistent chromosomal translocations in leukemias, helping to clarify some general principles, and supporting an instructive model of leukemogenesis. We hope that they will also prove useful for in vivo testing of new drugs before their translation into clinical use to further improve the treatment of leukemic patients.
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Funding |
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TopNotesAbstractIntroductionMouse Models of Chromosomal...MLL Translocation Mimics: Knock...MLL Translocation Mimics:...MLL Translocation Mimics:...The Mll-AF4 Protein Causes...ConclusionsFundingReferences |
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This work was funded by the Medical Research Council. MNL was the recipient of a Leukaemia Research Fund fellowship and MM of a fellowship from the German Research Foundation.
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NOTES |
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Present address: Department of Paediatrics, University of Erlangen, Loschgestr 15, 91054 Erlangen, Germany (M. Metzler).
Present address: ORYZON, Parc Cientific de Barcelona, Baldiri Reixac 15-21, 08028 Barcelona, Spain (M. N. Lobato).
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