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 <i>CEBPA</i>), especially in high-risk subtypes with <i>FLT3</i> mutations. We hypothesized that RNA activation (RNAa) of <i>CEBPA</i> 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 <i>CEBPA</i> 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 <i>in vitro</i> and <i>in vivo</i>. All together, these findings support RNAa of <i>CEBPA</i> as a potential adjuvant therapy for FLT3-mutated AML.