Increase of Sensitivity to Chemotherapy and NK-Mediated Cytotoxicity of Leukemic Stem Cell by a Farnesyltransferase Inhibitor.

Abstract 4161

Acute myeloid leukemia (AML) is a serious and often lethal hematopoietic malignant disease arising from stem cells. Leukemic stem cells (LSCs) play the central role in the relapse and refractory of AML and highlight the critical need for the new therapeutic strategies to directly target the LSC population. We previous found that LSC were resistant to chemotherapy and NK-mediated cytotoxicity, which were resulted from the apoptosis defect and NKG2D ligands change. Our previous data also showed that Manumycin induced apoptosis in leukemia cells through mitochondria pathway. Here, we demonstrated that manumycin increased the sensitivity of LSC to chemotherapy and NK cell-mediated cytotoxicity. Manumycin enhanced sensitivity to chemotherapy in LSCs via induced apoptosis. Analysis of signaling pathways revealed that manumycin enhanced mitoxantrone activation of caspase 3 and significantly decreasing Bcl2 protein. These finding indicated that manumycin sensitized mitoxantrone to chemotherapy via down-regulating Bcl2. Importantly, manumycin enhanced the sensitivities of LSCs to NK cells cytotoxicity through up-regulating the expressions of NKG2D ligands MICA/B and ULBP3. Thus, Manumycin present a promising novel therapeutic approach for AML therapy especially when resistant to chemotherapy and NK cell immunotherapy.