Cre-recombinase expression cooperates with FLT3ITD/ITD to induce acute myeloid leukemia [RNASeq_SclCre_JQ1_vs_vehicle]

Animal 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 utmost importance for difficult to treat leukemias such as FLT3-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 FLT3ITD/ITD 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. Mice were competitive transplanted with Scl-CreERT:Flt3ITD/ITD CD45.2 Kit+ spleenocytes leukemic splenocytes (5x10^6) mixed with CD45.1 C57BL/6 bone marrow (5x10^5). After 4 weeks high WBC was confirmed prior to treatment with JQ1 (50mg/kg) or vehicle. After 4 hours spleens were extracted and cells FACS sorted for (Kit+CD45.2+CD45.1-).