1. ¹MRC Laboratory of Molecular Biology, Cambridge, UK
2. ²Leeds Institute of Molecular Medicine, St James's University Hospital, Leeds, UK

Correspondence: Professor TH Rabbitts, Section of Experimental Therapeutics, Leeds Institute of Molecular Medicine, Wellcome Trust Brenner Building, St James's University Hospital, Leeds LS9 7TF, UK. E-mail: thr@leeds.ac.uk

³Current address: Cambridge Institute for Medical Research, Wellcome Trust/MRC Building, Addenbrooke's Hospital, Hills Road, Cambridge CB2 2XY, UK.

Received 2 July 2007; Revised 16 August 2007; Accepted 17 August 2007; Published online 1 October 2007.

Abstract

Chromosomal translocations involving the Mixed-Lineage Leukaemia (MLL) gene underlie many human leukaemias and MLL rearrangements are found in both acute myelogenous and acute lymphoblastic leukaemias. To assess the functionally relevant haematopoietic cell contexts for MLL fusions to be tumorigenic, we have generated different lines of mice in which de novo Mll-associated translocations occur. In these models, reciprocal chromosomal translocations occur by means of Cre-loxP-mediated recombination (translocator mice) in different cells of the haematopoietic system (namely haematopoietic stem cells, semi-committed progenitors or committed T or B cells). Translocations between Mll and Enl cause myeloid neoplasias, initiating in stem cells or progenitors while no tumours arose when the translocation was restricted to the B-cell compartment. Despite the absence of tumorigenesis, Mll-Enl translocations did occur and Mll-Enl fusion mRNA was expressed in B-cell-restricted translocators. A permissive cellular environment is therefore required for oncogenicity of Mll-associated translocations since the occurrence of Mll-Enl does not promote unrestricted proliferation in all haematopoietic cellular contexts, consistent with a specific instructive role of the MLL-fusion proteins in leukaemogenesis.