3108 – RNA ACTIVATION OF A TRANSCRIPTION FACTOR SUPPRESSES PROLIFERATION OF ACUTE MYELOID LEUKEMIA CELLS

Acute myeloid leukemia (AML) is the leading cause of adult leukemia deaths. Yet, many AML patients have no curative options or die immediately after intensive chemotherapy. Therefore, new treatment strategies are desperately needed. AML is characterized by the arrested differentiation and continued division of immature myeloid cells in the bone marrow. In a healthy state, myeloid cell differentiation is mediated by the master transcription factor C/EBPα encoded by the CEBPA gene. However, CEBPA is transcriptionally silenced in ∼30% of AML patients, leading to blocked differentiation. In fact, AML models show that increasing C/EBPα expression removes this differentiation block and halts leukemic cell division. Therefore, therapies that could specifically increase the expression of C/EBPα would be a promising AML treatment strategy. We hypothesize that RNA activation (RNAa) of CEBPA would reduce leukemic blast proliferation by inducing terminal differentiation, thus providing a new, less-toxic treatment option for these high-risk patients. To induce RNAa, we are using a chemically modified, short duplex RNA encapsulated into a liposomal nanoparticle, termed “MTL-CEBPA”. Here we report that MTL-CEBPA is selectively taken up by myeloid cells in vitro and in vivo and is functionally active once delivered. Specifically, MTL-CEBPA induces a >2-fold upregulation in CEBPA expression in AML cells. This CEBPA upregulation sensitizes AML cells to a commonly prescribed small molecule tyrosine kinase inhibitor, Gilteritinib, both in vitro and in a xenograft mouse model of human AML. Furthermore, MTL-CEBPA demonstrates an acceptable safety profile as reported in a recent phase Ib clinical trial for solid tumours (NCT02716012). Taken together, these results provide a proof-of-concept for the treatment of AML using RNAa.