Fan Yang,1 Hang Wu,1 Jing Yao,1 Xuelu Peng,1 Aiyun Yang,2 Tao Wen,1 Jie Meng,1 Jian Liu,1 Yu Zhang,3 Tao Wang,1 Haiyan Xu1,4 1Institute of Basic Medical Sciences 2Translational Medicine Laboratory, Beijing Key Laboratory of Child Development and Nutriomics, Capital Institute of Pediatrics, Beijing, Peopleâs Republic of China; 3State Key Laboratory of Bioelectronics, Jiangsu Key Laboratory for Biomaterials and Devices, School of Biological Science and Medical Engineering 4Beijing Key Laboratory of Key Technologies for Natural Drug Delivery and Novel Formulations, Institute of Materia Medica, Chinese Academy of Medical Sciences, Beijing, Peopleâs Republic of ChinaCorrespondence: Haiyan Xu; Tao Wang, Email xuhy@pumc.edu.cn; wangt@ibms.pumc.edu.cnIntroduction: Acute Myeloid Leukemia (AML) is characterized by the clonal expansion of undifferentiated myeloid precursors and is associated with notably higher incidence and mortality rates in the elderly population. While the BCL-2 inhibitor Venetoclax has transformed the therapeutic landscape for patients with AML who were ineligible for intensive therapy, primary and acquired resistance remained major obstacles to durable responses.Methods: In this study, an ultra-small Prussian Blue nanozyme (USPBNP)-based âmaturation-primingâ strategy was investigated to enhance Venetoclax sensitivity. USPBNPs were synthesized and characterized for physicochemical properties and enzyme-mimetic activities. Their differentiation-inducing effects were evaluated in Venetoclax-sensitive MOLM-13 cells, acquired-resistant RMOLM-13 cells, primary-resistant OCI-AML3 cells, murine C1498 AML cells, an AML1-ETO/KITD816V murine transplant model, and primary human AML bone marrow mononuclear cells. Cellular maturation was assessed by morphological analysis and flow-cytometric detection of lineage-associated markers. Venetoclax sensitization was evaluated by apoptosis assays, mitochondrial membrane potential analysis, and detection of apoptosis-related proteins.Results: In vitro, USPBNPs effectively reshaped the leukemic phenotype, driving differentiation in MOLM-13, RMOLM-13, and OCI-AML3 AML cells, evidenced by the reduced nucleo-cytoplasmic ratio as well as up-regulated CD11b, CD14, CD235a and CD41a. The âmaturation-primingâ effects were also confirmed through cross-species models in C1498 murine AML cells and a refractory AML1-ETO/KITD816V murine transplant mice model in vivo and in human clinical specimen. This phenotypic maturation lowered the apoptotic threshold of Venetoclax, resulting in mitochondrial membrane potential collapse, Caspase-3 activation, and the down-regulation of the resistance-associated protein MCL-1.Conclusion: These findings supported USPBNPs as a maturation-priming approach in AML models with distinct genetic backgrounds and Venetoclax resistance patterns. The combination of USPBNPs and Venetoclax coupled differentiation induction with apoptosis and might provide a potential strategy for improving Venetoclax responsiveness in AML.Keywords: acute myeloid leukemia, prussian blue nanozyme, differentiation, venetoclax, apoptosis
Yang et al. (Fri,) studied this question.