6.2 MLL-AF4 transgenic models
The MLL-AF4 fusion protein is seen in patients with t(4;11) and it is strongly associated with B-ALL. As early as 1996, J Corral et al. fused the AF9 sequence into the mouse MLL gene, and used the method of embryonic stem cell homologous recombination to create an MLL-AF9 gene knock-in model, and the chimeric mice carrying the fusion gene produced tumors(Corral et al., 1996). Based on the success of this model, researchers established an MLL-AF4 ”knock-in” transgenic model in which the majority of Mll-AF4 mice developed B-cell lymphoma after a long latency period(Chen, Li, Hudson, Kumar, Kirchhof & Kersey, 2006). In order to establish a mouse model more similar to human MLL-AF4, the researchers microinjected MLL-AF4 MSCV into the pronuclei of eggs from C57BL/6N Crj mice and established an MLL-AF4 transgenic mouse model by high expression of the human MLL-AF4 fusion gene. This is the first transgenic mouse to test the potential of human MLL-AF4 fusion protein to induce B-cell lymphoma/leukemia(Tamai et al., 2011). The above-mentioned MLL-AF4 Tg mouse models have also proved the effectiveness and feasibility of gene therapy for MLL-AF4+ALL and the specific mechanism, gene therapy is a promising strategy for the treatment of MLL-AF4+ALL(Tamai et al., 2012). Later, the researchers evaluated the potential of the anti-allergic drug amlexanox to improve the clinical efficacy of MLL-AF4+ALL and found that amlexanox reduced the resistance of MLL-AF4+ALL to TNFα by down-regulating the expression of S100A6(Tamai et al., 2017).
Another model was generated using an inverted AF4 allele targeted to an intronin the MLL gene. An AF4 cDNA flanked with loxP sites inserted in reverse orientation into the endogenous MLL locus,and then,cell-specific Cre expression was used to generate Mll-AF4 expression. Regardless of whether the Cre gene is controlled by a B-cell or T-cell promoter, mice develop B-cell lineage tumors only, but their phenotype is more mature than that normally observed in childhood leukemia(Metzler et al., 2006).