The MII-AF9 gene fusion in mice controls myeloproliferation and specifies acute myeloid leukaemogenesis

The MLL gene from human chromosome 11q23 is involved in >30 different chrom osomal translocations resulting in a plethora of different MLL fusion prote ins. Each of these tends to associate with a specific leukaemia type, for e xample, MLL-AF9 is found mainly in acute myeloid leukaemia. We have studied the role of the Mll-AF9 gene fusion made in mouse embryonic stem cells by an homologous recombination knock-in. Acute leukaemias developed in heteroz ygous mice carrying this fusion as well as in chimeric mice. As with human chromosomal translocation t(9;11), the majority of cases were acute myeloid leukaemias (AMLs) involving immature myeloblasts, but a minority were acut e lymphoblastic leukaemia. The AMLs were preceded by effects on haematopoie tic differentiation involving a myeloproliferation resulting in accumulatio n of Mac-1/Gr-1 double-positive mature myeloid cells in bone marrow as earl y as 6 days after birth. Therefore, non-malignant expansion of myeloid prec ursors is the first stage of Mll-AF9-mediated leukaemia followed by accumul ation of malignant cells in bone marrow and other tissues. Thus, the late o nset of overt tumours suggests that secondary tumorigenic mutations are nec essary for malignancy associated with MLL-AF9 gene fusion and that myelopro liferation provides the pool of cells in which such events can occur.