TY - JOUR AU - Min Wu, AU - Li Li, AU - Max Hamaker, AU - Donald Small, AU - Amy S. Duffield, PY - 2019/12/01 Y2 - 2024/03/29 TI - FLT3-ITD cooperates with Rac1 to modulate the sensitivity of leukemic cells to chemotherapeutic agents via regulation of DNA repair pathways JF - Haematologica JA - haematol VL - 104 IS - 12 SE - Articles DO - 10.3324/haematol.2018.208843 UR - https://haematologica.org/article/view/9166 SP - 2418-2428 AB - 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. ER -