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| Subject Categories: Development | Molecular Biology of Disease |
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| The EMBO Journal
(2005) 24, 3136–3146, doi:10.1038/sj.emboj.7600760 Published online 11 August 2005 |
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| Mll fusions generated by Cre-loxP-mediated de novo translocations can induce lineage reassignment in tumorigenesis |
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| Lesley F Drynan, Richard Pannell, Alan Forster, Nicole M M Chan, Florencia Cano, Angelika Daser and Terence H Rabbitts |
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MRC Laboratory of Molecular Biology, Cambridge, UK To whom correspondence should be addressed Terence H Rabbitts, MRC Laboratory of Molecular Biology, Hills Road, Cambridge CB2 2QH, UK. Tel.: +44 1223 402286; Fax: +44 1223 412178; E-mail: thr@mrc-lmb.cam.ac.uk Received 4 May 2005; Accepted 8 July 2005; Published online 11 August 2005. |
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| Abstract |
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| Chromosomal translocations are primary events in tumorigenesis. Those involving the mixed lineage leukaemia (MLL) gene are found in various guises and it is unclear whether MLL fusions can affect haematopoietic differentiation. We have used a model in which chromosomal translocations are generated in mice de novo by Cre-loxP-mediated recombination (translocator mice) to compare the functionally relevant haematopoietic cell contexts for Mll fusions, namely pluripotent stem cells, semicommitted progenitors or committed cells. Translocations between Mll and Enl or Af9 cause myeloid neoplasias, initiating in pluripotent stem cells or multipotent myeloid progenitors. However, while Mll-Enl translocations can also cause leukaemia from T-cell progenitors, no tumours arose with Mll-Af9 translocations in the T-cell compartment. Furthermore, Mll-Enl translocations in T-cell progenitors can cause lineage reassignment into myeloid tumours. Therefore, a permissive cellular environment is required for oncogenicity of Mll-associated translocations and Mll fusions can influence haematopoietic lineage commitment. |
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| Keywords: chromosomal translocations, Cre-loxP, ES cells, gene fusions, homologous recombination |
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