Activation of ERK and P38 by the Addition of Arsenic Trioxide in Flt3-ITD Cells

Flt3-internal tandem duplications (Flt3-ITD) is a prevalent mutation in acute myeloid leukemia (AML). We recently reported arsenic trioxide (ATO) and Flt3 inhibition synergize to induce apoptosis in Flt3-ITD cells. However, the signaling effect of ATO in these cells has not been elucidated. Here, we demonstrate that the treatment of ATO potently induces the activation of extracellular regulated kinase (ERK)- mitogen activated protein kinase (MAPK), and modestly activates p38-MAPK in BaF3-Flt3-ITD cells, among other major (PI3-kinase-Akt, c-jun N-terminal kinase [JNK]) signaling pathways examined. In contrast, in BaF3-Flt3-wild type (WT) cells, slight activation of p38, but none for others, was observed. As MAPK kinase (MEK), as well as p38 inhibition is reported to enhance ATO-induced apoptosis in AML and various hematological malignancies, our results suggest that Flt3 mutation status is important for the effect of these combinations.