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).