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

• 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
• ISSN: 0261-4189; 1460-2075
• DOI: 10.1038/sj.emboj.7600760

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.