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Small extracellular vesicles derived from acute myeloid leukemia cells promote leukemogenesis by transferring
Mengyu Li1, Guohuan Sun2, Jinlian Zhao3
1State Key Laboratory of Experimental Hematology; The Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), Department of Cell Biology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China; State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin.
Abstract:
Small extracellular vesicles (sEV) transfer cargos between cells and participate in various physiological and pathological processes through their autocrine and paracrine effects. However, the pathological mechanisms employed by sEV-encapsulated microRNA (miRNA) in acute myeloid leukemia (AML) are still obscure. In this study, we aimed to investigate the effects of AML cell-derived sEV (AML-sEV) on AML cells and delineate the underlying mechanisms. We initially used high-throughput sequencing to identify miR-221-3p as the miRNA prominently enriched in AML-sEV. Our findings revealed that miR-221-3p promoted AML cell proliferation and leukemogenesis by accelerating cell cycle entry and inhibiting apoptosis. Furthermore, Gbp2 was confirmed as a target gene of miR-221-3p by dual luciferase reporter assays and rescue experiments. Additionally, AML-sEV impaired the clonogenicity, particularly the erythroid differentiation ability, of hematopoietic stem and progenitor cells. Taken together, our findings reveal how sEV-delivered miRNA contribute to AML pathogenesis, which can be exploited as a potential therapeutic target to attenuate AML progression.
Insights
Small extracellular vesicles (sEVs) deliver microRNA-221-3p, promoting acute myeloid leukemia (AML) cell growth and impairing stem cell differentiation. This highlights sEV-miRNAs as potential therapeutic targets for AML.
Area of Science:
- Molecular Biology
- Cell Biology
- Oncology
Background:
- Small extracellular vesicles (sEVs) mediate intercellular communication.
- The role of microRNAs (miRNAs) within sEVs in acute myeloid leukemia (AML) pathogenesis is not fully understood.
Purpose of the Study:
- To investigate the impact of AML cell-derived sEVs (AML-sEVs) on AML cells.
- To identify specific miRNAs within AML-sEVs and elucidate their mechanisms of action.
Main Methods:
- High-throughput sequencing to identify enriched miRNAs in AML-sEVs.
- Dual luciferase reporter assays and rescue experiments to validate miRNA targets.
- Functional assays assessing AML cell proliferation, apoptosis, and hematopoietic stem/progenitor cell function.
Main Results:
- miR-221-3p was identified as highly enriched in AML-sEVs.
- miR-221-3p promotes AML cell proliferation and leukemogenesis by enhancing cell cycle entry and suppressing apoptosis.
- Gbp2 was validated as a direct target of miR-221-3p.
- AML-sEVs negatively affected hematopoietic stem and progenitor cell clonogenicity and erythroid differentiation.
Conclusions:
- sEV-delivered miR-221-3p plays a significant role in AML progression.
- Targeting sEV-encapsulated miRNAs presents a potential therapeutic strategy for AML.
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