Mll fusions generated by Cre-loxP-mediated de novo translocations can induce lineage reassignment in tumorigenesis

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 i...

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Bibliographic Details
Published in:	The EMBO journal Vol. 24; no. 17; pp. 3136 - 3146
Main Authors:	Drynan, Lesley F, Pannell, Richard, Forster, Alan, Chan, Nicole MM, Cano, Florencia, Daser, Angelika, Rabbitts, Terence H
Format:	Journal Article
Language:	English
Published:	Chichester, UK John Wiley & Sons, Ltd 07-09-2005 Blackwell Publishing Ltd
Subjects:	Animals Bone Marrow Cells - metabolism Bone Marrow Cells - pathology Cell Lineage - physiology Cell Transformation, Neoplastic - genetics Cell Transformation, Neoplastic - metabolism Cell Transformation, Neoplastic - pathology Cells, Cultured chromosomal translocations Cre-loxP DNA-Binding Proteins - genetics DNA-Binding Proteins - metabolism ES cells gene fusions Histone-Lysine N-Methyltransferase homologous recombination Integrases - genetics Integrases - metabolism Leukemia Leukemia, Lymphoid - metabolism Leukemia, Lymphoid - pathology Leukemia, Myeloid - metabolism Leukemia, Myeloid - pathology Mice Multipotent Stem Cells - metabolism Multipotent Stem Cells - pathology Myeloid Progenitor Cells - metabolism Myeloid Progenitor Cells - pathology Myeloid-Lymphoid Leukemia Protein Nuclear Proteins - genetics Nuclear Proteins - metabolism Oncogene Proteins, Fusion - genetics Oncogene Proteins, Fusion - metabolism Pluripotent Stem Cells - metabolism Pluripotent Stem Cells - pathology Proto-Oncogenes - genetics Recombination, Genetic Stem cells T-Lymphocytes - metabolism T-Lymphocytes - pathology Transcription Factors - genetics Transcription Factors - metabolism Translocation, Genetic - genetics Translocation, Genetic - physiology Tumors
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Summary:	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.
Bibliography:	Supplementary Table 1 istex:7B77FB949ABC5BB31DC815D5FD0712C5545E07B8 ark:/67375/WNG-N2PT6XDV-F ArticleID:EMBJ7600760 ObjectType-Article-2 SourceType-Scholarly Journals-1 ObjectType-Feature-1 content type line 23 ObjectType-Article-1 ObjectType-Feature-2
ISSN:	0261-4189 1460-2075
DOI:	10.1038/sj.emboj.7600760