Acute myeloid leukemia (AML) is a lethal hematologic malignancy. Chemotherapy resistance results in a dismal survival rate of 1–2 years in older adults with AML. Therefore, novel therapies are urgently required. In this context, microRNA (miRNA)-based treatments remain an untapped strategy in AML. Using patient-derived specimens, we found increased inflammatory cytokines, including interleukin-6 (IL-6) in the serum of older adults with AML, and decreased miR-497-5p in CD34+ leukemic blasts. Target prediction revealed that miR-497-5p could directly target mitogen-activated protein kinase-1 (MAP2K1) mRNA to indirectly target cytokines and the JAK/STAT signaling pathway through the p38-MAPK signaling pathway, potentially inhibiting leukemic growth and overcoming chemoresistance from venetoclax. To improve miRNA delivery and minimize off-target effects, which represent key barriers to clinical translation, we developed liposomes for co-delivery of miR-497-5p and venetoclax. We decorated our liposomes with a peptide targeting CLL1, which is present on 92% of leukemia blasts while being absent in normal hematopoietic cells. This targeted approach demonstrated high efficacy in inhibiting AML growth in mice with minimal toxicity, as well as reduced exposure to chemoresistance. Our findings suggested that anti-CLL1-decorated, miR-497-5p, and venetoclax-loaded liposomes represent a promising novel miRNA-based therapeutic, which should be investigated further as a strategy to reduce venetoclax resistance in AML.

中文翻译：

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载有 miR-497-5p 和维奈托克的抗 CLL1 脂质体作为急性髓性白血病的新型治疗策略


急性髓系白血病 （AML） 是一种致命的血液系统恶性肿瘤。化疗耐药性导致患有 AML 的老年人的 1-2 年生存率令人沮丧。因此，迫切需要新的疗法。在这种情况下，基于 microRNA （miRNA） 的治疗仍然是 AML 中尚未开发的策略。使用患者来源的标本，我们发现老年 AML 患者血清中的炎性细胞因子增加，包括白细胞介素 6 （IL-6），CD34+ 白血病母细胞中的 miR-497-5p 降低。靶点预测显示，miR-497-5p 可以直接靶向丝裂原活化蛋白激酶-1 （MAP2K1） mRNA，通过 p38-MAPK 信号通路间接靶向细胞因子和 JAK/STAT 信号通路，可能抑制白血病生长并克服维奈托克的化疗耐药性。为了改善 miRNA 递送并最大限度地减少脱靶效应，这是临床翻译的主要障碍，我们开发了用于共递送 miR-497-5p 和维奈托克的脂质体。我们用靶向 CLL1 的肽装饰我们的脂质体，该肽存在于 92% 的白血病原始细胞中，而在正常造血细胞中不存在。这种靶向方法在抑制小鼠 AML 生长方面表现出高效性，毒性最小，并且减少了化疗耐药性暴露。我们的研究结果表明，抗 CLL1 修饰的 miR-497-5p 和载有维奈托克的脂质体代表了一种很有前途的新型基于 miRNA 的治疗方法，应将其作为降低 AML 中维奈托克耐药性的策略进行进一步研究。