A conditional model of MLL-AF4 B-cell tumourigenesis using invertor technology.
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.
Metzler
M
M
MRC Laboratory of Molecular Biology, Cambridge, UK.
Forster
A
A
Pannell
R
R
Arends
M J
MJ
Daser
A
A
Lobato
M N
MN
Rabbitts
T H
TH
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
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