ANGPTL2-containing small extracellular vesicles from vascular endothelial cells accelerate leukemia progression
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
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
View: Text | PDF
Research Article Hematology

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

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

×

Figure 3

EC-SEVs support leukemia development.

Options: View larger image (or click on image) Download as PowerPoint
EC-SEVs support leukemia development. (A) Flow cytometry (left) and hist...
(A) Flow cytometry (left) and histogram (right) analysis of the percentage of YFP+ leukemia cells in the peripheral blood (PB) of recipients 20 days after transplantation (n = 5; the data represent the means ± SD; **P < 0.01, Student’s t test). (B) Recipient spleen and liver size (left) and weight (right) 20 days after transplantation (n = 3; the data represent the means ± SD; **P < 0.01, Student’s t test). (C) Flow cytometry (left) and histogram (right) analysis shows the percentages of L-GMP cells in the BM of recipients (n = 3; the data represent the means ± SD; **P < 0.01, Student’s t test). (D) Survival curves of Cdh5-CreER;Vps33bfl/fl mice and Vps33bfl/fl control mice after AML cell injection (n = 4–5; **P < 0.01, log-rank test). (E) The experimental procedure for BM EC isolation and coculture with AML cells. In brief, BM from Cdh5-CreER;Vps33bfl/fl mice or Vps33bfl/fl control mice was crushed and digested, and enriched using anti-CD31 beads. The enriched ECs were transduced with AKT lentiviruses and cocultured with AML cells for 3 days. After coculture, the AML cells were injected into C57BL/6J recipients. (F) Left: The morphology of the enriched and cultured ECs. Scale bar: 40 μm. Right: Flow cytometry analysis to determine the purity of cultured ECs. (G) Survival curves of C57BL/6J recipients injected with AML cells cocultured with WT ECs or Vps33b-null ECs (n = 5; **P < 0.01, log-rank test). Experiments were conducted 2–4 times for validation.