An Mll–AF9 Fusion Gene Made by Homologous Recombination Causes Acute Leukemia in Chimeric Mice: A Method to Create Fusion Oncogenes

Abstract

Homologous recombination in embryonal stem cells has been used to produce a fusion oncogene, thereby mimicking chromosomal translocations that frequently result in formation of tumor-specific fusion oncogenes in human malignancies. AF9 sequences were fused into the mouse Mll gene so that expression of the Mll-AF9 fusion gene occurred from endogenous Mll transcription control elements, as in t(9;11) found in human leukemias. Chimeric mice carrying the fusion gene developed tumors, which were restricted to acute myeloid leukemias despite the widespread activity of the Mll promoter. Onset of perceptible disease was preceded by expansion of ES cell derivatives in peripheral blood. This novel use of homologous recombination formally proves that chromosomal translocations contribute to malignancy and provides a general strategy to create fusion oncogenes for studying their role in tumorigenesis.

The cloning, mapping and expression of a novel gene, BRL, related to the AF10 leukaemia gene

“…These translocations result in in-frame fusions suggesting an important role for the di erent COOH regions in the oncogenic transformation. This is supported by the demonstration that a germline fusion between MLL and AF9, created by homologous recombination, results in leukaemias in chimeric mice (Corral et al, 1996).…”

AF15q14, a novel partner gene fused to the MLL gene in an acute myeloid leukaemia with a t(11;15)(q23;q14)

“…The apparentlyinsigni®cant role of the partner genes in leukaemogenesis is suggested by the tandem duplication of the MLL gene, whose e ects are similar to those of translocations, and by a recent study which showed that truncated MLL, when fused to the bacterial Lac Z gene, is su cient for tumorigenesis (Dobson et al, 2000). However, the contribution of the partner gene to leukaemogenesis could still be critical, in view of a mouse knock-in study which has shown that MLL-AF9 chimeras develop AML, whereas MLL-myc chimeras do not (Corral et al, 1996). Moreover, the immortalization of murine haematopoietic progenitors by the retrovirus-mediated gene transfer of MLL-ENL requires the integrity of the transactivation activity of ENL (Schreiner et al, 1999).…”

Leukemia-associated genetic aberrations in mesenchymal stem cells of children with acute lymphoblastic leukemia

“…The MLL fusion proteins disrupt the normal pattern of expression of HOX genes, causing change in the self-renewal and growth of HSC and committed progenitors. Murine models of MLL-induced leukemia confirmed the oncogenic role of MLL fusion proteins (29,30).…”