RNA activation of CEBPA improves leukemia treatment.

Acute myeloid leukemia (AML) is a highly aggressive blood cancer marked by impaired differentiation and uncontrolled proliferation of myeloid cells. This phenotype is often driven by dysregulated expression of the transcription factor C/EBPα (encoded by CEBPA), especially in high-risk subtypes with FLT3 mutations. We hypothesized that RNA activation (RNAa) of CEBPA could reduce the growth of FLT3-mutated AML, and synergize with currently approved FLT3 inhibitors, thereby offering an alternative treatment strategy for a deadly disease. Our study shows that MTL-CEBPA, a chemically modified small activating RNA encapsulated in NOV340 liposomes, selectively targets myeloid cells, boosts CEBPA expression, and promotes a non-proliferative, mature state in FLT3-mutated AML cells. Importantly, MTL-CEBPA enhances the efficacy of commonly prescribed FLT3 inhibitor, gilteritinib, both in vitro and in vivo. All together, these findings support RNAa of CEBPA as a potential adjuvant therapy for FLT3-mutated AML.