Kovecses Olivia, Sharif-Askari Bahram, Gonzalez-Losada Cristobal, Reebye Vikash, Ryan Bríd M, Luedtke Nathan W, Mercier François E, McKeague Maureen
Department of Pharmacology & Therapeutics, McGill University, Montreal, Québec H3G 1Y6, Canada.
Lady Davis Institute for Medical Research & Cancer Segal Center, Jewish General Hospital, Montreal, Québec H3T 1E1, Canada.
Mol Ther Nucleic Acids. 2025 Jun 16;36(3):102611. doi: 10.1016/j.omtn.2025.102611. eCollection 2025 Sep 9.
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 ), especially in high-risk subtypes with mutations. We hypothesized that RNA activation (RNAa) of 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 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 and . All together, these findings support RNAa of as a potential adjuvant therapy for FLT3-mutated AML.
急性髓系白血病（AML）是一种侵袭性很强的血癌，其特征是髓系细胞分化受损和不受控制的增殖。这种表型通常由转录因子C/EBPα（由 编码）的表达失调驱动，特别是在具有 突变的高危亚型中。我们假设对 的RNA激活（RNAa）可以减少FLT3突变型AML的生长，并与目前批准的FLT3抑制剂协同作用，从而为这种致命疾病提供一种替代治疗策略。我们的研究表明，MTL-CEBPA是一种包裹在NOV340脂质体中的化学修饰小激活RNA，它选择性地靶向髓系细胞，提高 表达，并促进FLT3突变型AML细胞进入非增殖性成熟状态。重要的是，MTL-CEBPA在体内和体外均增强了常用的FLT3抑制剂吉瑞替尼的疗效。总之，这些发现支持将对 的RNAa作为FLT3突变型AML的一种潜在辅助治疗方法。
