Combination of PP242 and dasatinib suppresses the progression of acute myeloid leukemia in a mouse model

Abstract

Objective: To establish the acute myeloid leukemia (AML) mouse model, and to preliminarily investigate the efficiency of dasatinib, a tryosine kinase inhibitor, and PP242, an inhibitor of PI3K/Akt/mTOR signaling pathway in the development of AML. Methods: The lineage(-) (Lin(-)) cells of C57BL/6J were transduced with retrovirus carrying MSCV-MLL-AF9-IRES-GFP fusion gene. The transduced cells were transplanted into lethally irradiated recipient mice to induce AML, and then the AML mouse model were established. The leukemia mice were treated with vehicle, dasatinib, PP242, dasatinib+ PP242, separately. The survival of the recipient mice was observed and the percentage of leukemia cells in peripheral blood (PB) and bone marrow (BM) was examined every four days. The apoptosis rates and cell cycle status of leukemia cells were also examined by FLOW. The leukemia cells in different group were sorted, the mRNA of these leukemia were extracted and reverse transcripted for related gene expression by qRT-PCR. The molecular mechanism of supression of leukemia cells growth was studied via RNA-Seq experiments. Results: Compared with control group, either PP242 or dasatinib could prolong the survival rate of recipient mice, however, the combination treatment AML mice with PP242 and dasatinib prolonged the life span of AML mice more significantly. The combination of PP242 and dasatinib could decrease the percentage of leukemia cells in PB and BM more significantly, arresting more leukemia cells in G0 phase, inducing more apoptosis of leukemia cells. Conclusion: Combination of tryosine kinase inhibitor-dasatinib and PI3K/Akt/mTOR signaling pathway inhibitor- PP242 could delay the progression of AML by inducing more leukemia to apoptosis and arrest more leukemia cells in the cell cycle G0 phase, it may be provied a new method for clinical therapy.