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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.

Original publication

DOI

10.1038/sj.emboj.7600760

Type

Journal article

Journal

EMBO J

Publication Date

07/09/2005

Volume

24

Pages

3136 - 3146

Keywords

Animals, Bone Marrow Cells, Cell Lineage, Cell Transformation, Neoplastic, Cells, Cultured, DNA-Binding Proteins, Histone-Lysine N-Methyltransferase, Integrases, Leukemia, Lymphoid, Leukemia, Myeloid, Mice, Multipotent Stem Cells, Myeloid Progenitor Cells, Myeloid-Lymphoid Leukemia Protein, Nuclear Proteins, Oncogene Proteins, Fusion, Pluripotent Stem Cells, Proto-Oncogenes, Recombination, Genetic, T-Lymphocytes, Transcription Factors, Translocation, Genetic