FLT3-ITD cooperates with Rac1 to modulate the sensitivity of leukemic cells to chemotherapeutic agents via regulation of DNA repair pathways.

Abstract

Acute myeloid leukemia (AML) is an aggressive hematologic neoplasm, and patients with an internal tandem duplication (ITD) mutation of the FMS-like tyrosine kinase-3 (FLT3) receptor gene have a poor prognosis. FLT3-ITD interacts with DOCK2, a G effector protein that activates Rac1/2. Previously, we showed that knockdown of DOCK2 leads to decreased survival of FLT3-ITD leukemic cells. We further investigated the mechanisms by which Rac1/DOCK2 activity affects cell survival and chemotherapeutic response in FLT3-ITD leukemic cells. Exogenous expression of FLT3-ITD led to increased Rac1 activity, reactive oxygen species, phosphorylated STAT5, DNA damage response factors and cytarabine resistance. Conversely, DOCK2 knockdown resulted in a decrease in these factors. Consistent with the reduction in DNA damage response factors, FLT3-ITD cells with DOCK2 knockdown exhibited significantly increased sensitivity to DNA damage response inhibitors. Moreover, in a mouse model of FLT3-ITD AML, animals treated with the CHK1 inhibitor MK8776 + cytarabine survived longer than those treated with cytarabine alone. These findings suggest that FLT3-ITD and Rac1 activity cooperatively modulate DNA repair activity, the addition of DNA damage response inhibitors to conventional chemotherapy may be useful in the treatment of FLT3-ITD AML, and inhibition of the Rac signaling pathways via DOCK2 may provide a novel and promising therapeutic target for FLT3-ITD AML.