transgenic models
The BCR-ABL fusion protein is the result of t(9;22)(q34;q11) translocation, which is common in CML, but can also be found in B cell ALL. There are several isoforms of this fusion protein, including the P210 form and the P190 form, with the P120 form progressing to B and T lymphoma or myeloid leukemia after a longer latency period and the P190 form progressing to B-ALL(Voncken, Kaartinen, Pattengale, Germeraad, Groffen & Heisterkamp, 1995).
Researchers injected patients’ BM cells which transfected with MSCV BCR-ABL1 lentivirus into C57BL/6 mice, and used this mouse model to determine the important role of tumor suppressor γ-catenin in the initiation and maintenance of BCR-ABL1+B-ALL, determining the potential therapeutic target for the treatment of BCR-ABL1+B-ALL(Luong-Gardiol et al., 2019). Cyclin-dependent kinase (CDK) is a promising drug target in cancer treatment, the loss of CDK8 significantly prolonged disease latency and inhibited disease progression(Menzl et al., 2019). Through the BCR-ABL transgenic mouse model, researchers found that CDK8 played a key role in B-ALL, and degradation of CDK8 might be a potential therapeutic strategy for the treatment of ALL. InLong non-coding RNAs(lncRNA)-Iur knockout transgenic mice, researchers explored the functional relevance between aberrantly expressed lncRNAs and BCR-ABL-mediated leukemia(Wang et al., 2019).
This model has explored the effect of obesity on the progression of ALL. For the first time, it was found that obesity could accelerate the development of ALL, in a controlled experiment between BCR/ABL transgenic mice and high-fat diet AKR/J mice(Yun et al., 2010). In addition, this model was also used to test the activity of tyrosine kinase inhibitors. The 8093ALL cell line was established in the background of P190 BCR-ABL transgenic mice and transplanted into C57BL/6J mice. It was found that nilotinib was significantly more effective than imatinib and was able to eliminate a significant number of ALL cells in vivo (Kaur et al., 2007). Later, researchers induced BCR-ABL expression in mice by the Tet-OFF system, and treatment with nilotinib reduced the number of leukemic cells and prolonged survival in mice. This suggests that combined inhibition of BCL-2 and BCL-ABL tyrosine kinases has the potential to significantly improve the cure rate of CML, while tyrosine kinase inhibitors targeting BCL-2 and BCL-ABL can overcome this limitation of disease relapse(Carter et al., 2016). These findings are of great significance for adjusting clinical treatment plans and improving patient prognosis.