CD64-targeted HO-1 RNA interference enhances chemosensitivity in orthotopic model of acute myeloid leukemia and patient-derived bone marrow cells.

Abstract

Acute myeloid leukemia is the most frequent and life-threatening blood cancer. The main treatment is chemotherapy, sometimes followed by stem cell transplant. Resistance to chemotherapy and hepatotoxicity of the CD33-targeted therapy require an alternative therapeutic strategy. Here, we report CD64-targeted RNA interference as a novel AML therapy, which was delivered by a recombinant fusion protein of CD64-binding antibody and nona-arginine (sR9). The sR9-mediated heme oxygenase-1 siRNA (siHO-1) delivery efficiently enhanced apoptotic response to daunorubicin of AML cells and AML-targeted HO-1 silencing improved chemotherapy and prolonged survival in orthotopic myeloid leukemia model. CD64 expression was verified and HO-1-silencing-mediated chemo-sensitization was also validated in leukemic blast cells originated from AML M4/M5 patient's bone marrow. Collectively, CD64-targeted RNA interference could be a promising strategy for AML therapy and AML-targeted HO-1 suppression is expected to improve the chemotherapeutic effect in future clinical trials.