QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia.
The University of Queensland, Brisbane, QLD, Australia.
Leukemia. 2023 Apr;37(4):741-750. doi: 10.1038/s41375-023-01832-0. Epub 2023 Feb 4.
Murine models offer a valuable tool to recapitulate genetically defined subtypes of AML, and to assess the potential of compound mutations and clonal evolution during disease progression. This is of particular importance for difficult to treat leukemias such as FLT3 internal tandem duplication (ITD) positive AML. While conditional gene targeting by Cre recombinase is a powerful technology that has revolutionized biomedical research, consequences of Cre expression such as lack of fidelity, toxicity or off-target effects need to be taken into consideration. We report on a transgenic murine model of FLT3-ITD induced disease, where Cre recombinase expression alone, and in the absence of a conditional allele, gives rise to an aggressive leukemia phenotype. Here, expression of various Cre recombinases leads to polyclonal expansion of FLT3 progenitor cells, induction of a differentiation block and activation of Myc-dependent gene expression programs. Our report is intended to alert the scientific community of potential risks associated with using this specific mouse model and of unexpected effects of Cre expression when investigating cooperative oncogenic mutations in murine models of cancer.
鼠模型提供了一种有价值的工具，可以重现 AML 中基因定义的亚型，并评估在疾病进展过程中复合突变和克隆进化的潜力。这对于治疗困难的白血病（如 FLT3 内部串联重复（ITD）阳性 AML）尤为重要。虽然 Cre 重组酶的条件基因靶向是一项革命性的生物医学研究技术，但 Cre 表达的后果，如保真度、毒性或脱靶效应，需要加以考虑。我们报告了一种 FLT3-ITD 诱导疾病的转基因鼠模型，其中 Cre 重组酶的表达本身，而没有条件等位基因，会导致侵袭性白血病表型。在这里，各种 Cre 重组酶的表达导致 FLT3 祖细胞的多克隆扩增，诱导分化阻滞和 Myc 依赖性基因表达程序的激活。我们的报告旨在提醒科学界注意使用这种特定小鼠模型的相关风险，并注意在研究癌症的鼠模型中的协同致癌突变时 Cre 表达的意外作用。
