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ANGPTL2-containing small extracellular vesicles from vascular endothelial cells accelerate leukemia progression
Dan Huang, … , Junke Zheng, Tao Cheng
Dan Huang, … , Junke Zheng, Tao Cheng
Published October 27, 2020
Citation Information: J Clin Invest. 2021;131(1):e138986. https://doi.org/10.1172/JCI138986.
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Research Article Hematology Article has an altmetric score of 17

ANGPTL2-containing small extracellular vesicles from vascular endothelial cells accelerate leukemia progression

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Abstract

Small extracellular vesicles (SEVs) are functional messengers of certain cellular niches that permit noncontact cell communications. Whether niche-specific SEVs fulfill this role in cancer is unclear. Here, we used 7 cell type–specific mouse Cre lines to conditionally knock out Vps33b in Cdh5+ or Tie2+ endothelial cells (ECs), Lepr+ BM perivascular cells, Osx+ osteoprogenitor cells, Pf4+ megakaryocytes, and Tcf21+ spleen stromal cells. We then examined the effects of reduced SEV secretion on progression of MLL-AF9–induced acute myeloid leukemia (AML), as well as normal hematopoiesis. Blocking SEV secretion from ECs, but not perivascular cells, megakaryocytes, or spleen stromal cells, markedly delayed the leukemia progression. Notably, reducing SEV production from ECs had no effect on normal hematopoiesis. Protein analysis showed that EC-derived SEVs contained a high level of ANGPTL2, which accelerated leukemia progression via binding to the LILRB2 receptor. Moreover, ANGPTL2-SEVs released from ECs were governed by VPS33B. Importantly, ANGPTL2-SEVs were also required for primary human AML cell maintenance. These findings demonstrate a role of niche-specific SEVs in cancer development and suggest targeting of ANGPTL2-SEVs from ECs as a potential strategy to interfere with certain types of AML.

Authors

Dan Huang, Guohuan Sun, Xiaoxin Hao, Xiaoxiao He, Zhaofeng Zheng, Chiqi Chen, Zhuo Yu, Li Xie, Shihui Ma, Ligen Liu, Bo O. Zhou, Hui Cheng, Junke Zheng, Tao Cheng

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Figure 7

VPS33B regulates ANGPTL2-SEV release.

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VPS33B regulates ANGPTL2-SEV release.
(A) Western blot analysis of ANGPT...
(A) Western blot analysis of ANGPTL2, TSG101, FLOT1, and VPS33B protein levels in BM fluid SEVs from Vps33bfl/fl mice and Cdh5-Cre;Vps33bfl/fl mice. (B) Colocalization of CD63 and ANGPTL2 in WT and VPS33B-null ECs. (C) Flow cytometry (left) and histogram (right) analysis of the percentages of YFP+ AML cells in the PB of the indicated recipients injected with AML cells cocultured with Ctrl-SEVs or ANGPTL2-SEVs (n = 5; the data represent the means ± SD; *P < 0.05, **P < 0.01, ***P < 0.001, 1-way ANOVA with Tukey’s multiple-comparison test). (D) Survival analysis of the indicated recipients injected with AML cells cocultured with Ctrl-SEVs or ANGPTL2-SEVs (3 μg per 1 × 105 AML cells) (n = 5; *P < 0.05, **P < 0.01, log-rank test). (E) The in vivo administration of ANGPTL2-SEVs into Cdh5-Cre;Vps33bfl/fl mice and Vps33bfl/fl control recipients. Equal volumes of Ctrl- or ANGPTL2-SEVs (20 μg) were intratibially injected every 5 days for 20 days. (F) Survival analysis of AML recipients injected with Ctrl- or ANGPTL2-SEVs (n = 5; *P < 0.05, **P < 0.01, log-rank test). (G) The percentage of L-GMP cells in BM of indicated recipients (n = 5; the data represent the means ± SD; *P < 0.05, **P < 0.01, 1-way ANOVA with Tukey’s multiple-comparison test). Experiments were conducted 2 times for validation.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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