Conditional transgenic technologies

Ryding, Alisdair; Sharp, Michael; Mullins, John J.

doi:10.1677/joe.0.1710001

Cited by 141 publications

(105 citation statements)

References 125 publications

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“…Although these results are insightful, the approach has several intrinsic disadvantages, most notably the unrestricted expression pattern of the mutated gene. Consequently, several methods were developed for conditional or inducible in vivo gene expression, the details of which are described in several noteworthy reviews (Muller, 1999;Testa and Stewart, 2000;Ryding et al, 2001;Yu and Bradley, 2001;Bockamp et al, 2002;van der Weyden et al, 2002).…”

Section: Knock-in Modelsmentioning

confidence: 99%

“…The tetracycline (tet-) inducible (Gossen and Bujard, 1992;Gossen et al, 1995;Jaisser, 2000;Ryding et al, 2001) and Cre/loxPmediated (Muller, 1999;Jaisser, 2000;Testa and Stewart, 2000;Ryding et al, 2001;Yu and Bradley, 2001) interchromosomal translocation recombination systems have been utilized in generation of inducible models of AML1/ETO t(8;21) (Buchholz et al, 2000;Higuchi et al, 2002;Rhoades et al, 2000), MLL-CBP t(11;16) , MN1-TEL t(12 ;22) (Kawagoe and Grosveld, 2005) and MLL/AF9 t(9;11) (Collins et al, 2000). In both the tet-off and Cre-loxP models of AML1/ETO (Rhoades et al, 2000;Higuchi et al, 2002), the transcriptional control of AML1/ETO fusion protein was highly expressed in bone marrow, however, as noted in the hMRP8-AML1/ETO model, there was no development of leukaemic phenotype unless expressed with cooperating mutations.…”

Section: Conditional Knock-inmentioning

confidence: 99%

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Review: genetic models of acute myeloid leukaemia

2008

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The use of genetically engineered mice (GEM) have been critical in understanding disease states such as cancer, and none more so than acute myelogenous leukaemia (AML), a disease characterized by over 100 distinct chromosomal translocations. A substantial proportion of cases exhibiting recurrent reciprocal translocations at diagnosis, such as t(8;21) or t(15;17) have been exhaustively studied and are currently employed in clinical diagnosis. However, a definitive conclusion regarding the leukaemogenic potential of defined transgenes for this disease remains elusive. While it is increasingly apparent that a number of cooperating mutations are necessary to develop a leukaemic phenotype, the number of models reflecting these synergisms remains few. Furthermore, little emphasis has been paid to the effect of chromosomal translocations other than recurrent genetic abnormalities, with no models reflecting the multiple abnormalities observed in high-risk cases of AML accounting for 8-10% of adult AML. Here we review the differing technologies employed in generation of GEM of AML. We discuss the relevance of GEM AML from embryonic stem cell-mediated (for example retinoic acid receptor-a fusions and AML1/ETO) models; through to the valuable retroviral-mediated gene transfer models. The latter have been used to great effect in defining the transforming properties of chromosomal translocation products such as MLL (found in 5-6% of all AML cases) and NUP98 (denoting poor prognosis in therapy-related disease) and particularly when co-transduced with bad prognostic factors such as Flt3 mutations. Finally, we comment on the emergence of newer transduction technologies, which can regulate the level of expression to defined cell lineages in both primary murine and human xenografts, and discuss how combining multiple genetic modalities, more relevant models of this complex disease are being generated.

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Section: Knock-in Modelsmentioning

confidence: 99%

Section: Conditional Knock-inmentioning

confidence: 99%

Review: genetic models of acute myeloid leukaemia

2008

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“…Conse- Table 4 Distribution of translocation-generated oncogenes and associated models FAB classification (% of human cases) 4,109 Translocations (% of human cases) 4,109 Genes involved Transgenic models Review: Animal models of AML E Mc Cormack et al quently, several methods were developed for conditional or inducible in vivo gene expression, the details of which are described in several noteworthy reviews. [420][421][422][423][424][425] A modification of the knockin approach targets mutated genes into loci other than that of the involved gene and whose expression is restricted to the cell type where the aberrant gene is expressed in the human disease. Employing this methodology, a knockin model of PML/RARa t(15;17) using the endogenous murine cathepsin G-promoter was generated with 90% incidence of APML in comparison to only 15-20% prevalence observed in the relative hCG-PML/RARa model with similar pathology.…”

Section: Knockin Micementioning

confidence: 99%

“…Employing this methodology, a knockin model of PML/RARa t(15;17) using the endogenous murine cathepsin G-promoter was generated with 90% incidence of APML in comparison to only 15-20% prevalence observed in the relative hCG-PML/RARa model with similar pathology. 408 The tetracycline (tet-) inducible 424,[426][427][428] and Cre/loxPmediated 420,421,424,425,428 interchromasomal translocation recombination systems have been utilised in generation of inducible models of AML1/ETO t(8;21) [429][430][431] and MLL/AF9 t(9;11). 432 In both the tet-off and Cre-loxP models for AML1/ ETO, 430,431 the transcriptional control of AML1/ETO fusion protein was highly expressed in bone marrow; however, as noted in the hMRP8-AML1/ETO model, there was no development of leukaemic phenotype unless expressed in tandem with cooperating mutations.…”

Section: Knockin Micementioning

confidence: 99%

Animal models of acute myelogenous leukaemia – development, application and future perspectives

2005

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From the early inception of the transplant models through to contemporary genetic and xenograft models, evolution of murine leukaemic model systems have been critical to our general comprehension and treatment of cancer, and, more specifically, disease states such as acute myelogenous leukaemia (AML). However, even with modern advances in therapeutics and molecular diagnostics, the majority of AML patients die from their disease. Thus, in the absence of definitive in vitro models which precisely recapitulate the in vivo setting of human AMLs and failure of significant numbers of new drugs late in clinical trials, it is essential that murine AML models are developed to exploit more specific, targeted therapeutics. While various model systems are described and discussed in the literature from initial transplant models such as BNML and spontaneous murine leukaemia virus models, to the more definitive genetic and clinically significant NOD/SCID xenograft models, there exists no single compendium which directly assesses, reviews or compares the relevance of these models. Thus, the function of this article is to provide clinicians and experimentalists a chronological, comprehensive appraisal of all AML model systems, critical discussion on the elucidation of their roles in our understanding of AML and consideration to their efficacy in the development of AML chemotherapeutics.

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“…In addition, we will present a novel database compiling already established tissue-specific effector mice for conditionally expressing recombinant genes using the "tet on/off" system. It is not intended to be comprehensive, and the reader is encouraged to explore other excellent recent reviews on this topic (50,84,117,153).…”

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confidence: 99%

Of mice and models: improved animal models for biomedical research

Bockamp

Maringer

Spangenberg

et al. 2002

Physiological Genomics

147

109

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The ability to engineer the mouse genome has profoundly transformed biomedical research. During the last decade, conventional transgenic and gene knockout technologies have become invaluable experimental tools for modeling genetic disorders, assigning functions to genes, evaluating drugs and toxins, and by and large helping to answer fundamental questions in basic and applied research. In addition, the growing demand for more sophisticated murine models has also become increasingly evident. Good state-of-principle knowledge about the enormous potential of second-generation conditional mouse technology will be beneficial for any researcher interested in using these experimental tools. In this review we will focus on practice, pivotal principles, and progress in the rapidly expanding area of conditional mouse technology. The review will also present an internet compilation of available tetracycline-inducible mouse models as tools for biomedical research ( http://www.zmg.uni-mainz.de/tetmouse/ ).

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Conditional transgenic technologies

Cited by 141 publications

References 125 publications

Review: genetic models of acute myeloid leukaemia

Review: genetic models of acute myeloid leukaemia

Animal models of acute myelogenous leukaemia – development, application and future perspectives

Of mice and models: improved animal models for biomedical research

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