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Anti-CLL1 liposome loaded with miR-497-5p and venetoclax as a novel therapeutic strategy in acute myeloid leukemia


. 2024 Oct 4:S1525-0016(24)00659-2.


doi: 10.1016/j.ymthe.2024.09.036.


Online ahead of print.

Affiliations

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Qiaoyu Pan et al.


Mol Ther.


.

Abstract

Acute myeloid leukemia (AML) is a lethal hematologic malignancy. Chemotherapy resistance results in a dismal survival 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 IL-6 in 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 JAK/STAT signaling pathway through 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% 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 further investigated as a strategy to reduce venetoclax resistance in AML.

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