title: A conditional model of MLL-AF4 B-cell tumourigenesis using invertor technology.
abstract: MLL-AF4 fusion is the most common consequence of chromosomal translocations in infant leukaemia and is associated with a poor prognosis. MLL-AF4 is thought to be required in haematopoietic stem cells to elicit leukaemia and may be involved in tumour phenotype specification as it is only found in B-cell tumours in humans. We have employed the invertor conditional technology to create a model of MLL-AF4, in which a floxed AF4 cDNA was knocked into Mll in the opposite orientation for transcription. Cell-specific Cre expression was used to generate Mll-AF4 expression. The mice develop exclusively B-cell lineage neoplasias, whether the Cre gene was controlled by B- or T-cell promoters, but of a more mature phenotype than normally observed in childhood leukaemia. These findings show that the MLL-AF4 fusion protein does not have a mandatory role in multi-potent haematopoietic stem cells to cause cancer and indicates that MLL-AF4 has an instructive function in the phenotype of the tumour.
authors.affiliation: MRC Laboratory of Molecular Biology, Cambridge, UK.
authors.forename: M
authors.initials: M
authors.lastname: Metzler
authors.forename: A
authors.initials: A
authors.lastname: Forster
authors.forename: R
authors.initials: R
authors.lastname: Pannell
authors.forename: M J
authors.initials: MJ
authors.lastname: Arends
authors.forename: A
authors.initials: A
authors.lastname: Daser
authors.forename: M N
authors.initials: MN
authors.lastname: Lobato
authors.forename: T H
authors.initials: TH
authors.lastname: Rabbitts
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000378:metabolism / Q000473:pathology*; D019070:Cell Lineage; D002471:Cell Transformation, Neoplastic; D005260:Female; D005804:Genes, Lethal; D018398:Homeodomain Proteins / Q000235:genetics / Q000502:physiology; D006801:Humans; D019426:Integrases / Q000378:metabolism; D016393:Lymphoma, B-Cell / Q000235:genetics / Q000473:pathology*; D016403:Lymphoma, Large B-Cell, Diffuse / Q000235:genetics / Q000473:pathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D051788:Myeloid-Lymphoid Leukemia Protein / Q000235:genetics / Q000502:physiology*; D015514:Oncogene Proteins, Fusion / Q000235:genetics / Q000502:physiology*; D010641:Phenotype; D013601:T-Lymphocytes / Q000378:metabolism / Q000473:pathology
chemical_list: D018398:Homeodomain Proteins; C113855:MLL-AF4 fusion protein, human; D015514:Oncogene Proteins, Fusion; C064658:RAG-1 protein; D051788:Myeloid-Lymphoid Leukemia Protein; C045073:Cre recombinase; D019426:Integrases