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JNCI Monographs 2008 2008(39):58-63; doi:10.1093/jncimonographs/lgn022
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© The Author 2008. Published by Oxford University Press.

Modeling Chromosomal Translocations Using Conditional Alleles to Recapitulate Initiating Events in Human Leukemias

M. Natividad Lobato, Markus Metzler, Lesley Drynan, Alan Forster, Richard Pannell, Terence H. Rabbitts

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).

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.

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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