1. ¹MRC Laboratory of Molecular Biology, Cambridge, UK
2. ²Department of Pathology, University of Cambridge, Cambridge, UK

Correspondence: Dr TH Rabbitts, MRC Laboratory of Molecular Biology, Hills Road, Cambridge CB2 2QH, UK. E-mail: thr@mrc-lmb.cam.ac.uk

Received 8 February 2006; Revised 22 March 2006; Accepted 22 March 2006; Published online 10 April 2006.

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.