Mutations in FMS-like tyrosine kinase 3 (FLT3) are among the most common in myeloid blood cancers.
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. Here, expression of various Cre recombinases leads to polyclonal expansion of FLT3 ITD/ITD progenitor cells, induction of a differentiation block and activation of Myc-dependent gene expression programs. 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. 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. This is of particular importance for difficult to treat leukemias such as FLT3 internal tandem duplication (ITD) positive AML.
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.
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