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
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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

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Figure 4

EC-SEVs have no effect on normal hematopoiesis.

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EC-SEVs have no effect on normal hematopoiesis. (A–C) Cellularity analys...
(A–C) Cellularity analysis of Cdh5-CreER;Vps33bfl/fl mice and Vps33bfl/fl littermate control mice. The total BM cell numbers (A), frequencies of hematopoietic progenitor cells (B), and frequencies of HSCs/multipotent progenitors (MPPs) (C) are shown (n = 4–6; the data represent the means ± SD, Student’s t test). (D) The percentage of CD45.2+ donor cells in the PB of recipient mice at the indicated time points after competitive BM transplantation. The donor cells from Cdh5-CreER;Vps33bfl/fl mice and Vps33bfl/fl littermate control mice were CD45.2+ (n = 10; the data represent the means ± SEM, Student’s t test). (E) The short-term and long-term multilineage reconstitution capacities of donor-derived (CD45.2) PB cells in recipients (n = 6; Student’s t test). (F) The percentage of CD45.2+ donor-derived HSCs in the BM of recipients (n = 6; the data represent the means ± SD, Student’s t test). (G) The percentage of CD45.1+ donor cells in the PB of recipient mice at the indicated time points after BM transplantation. The donor cells were CD45.1+ (n = 10; the data represent the means ± SEM, Student’s t test). (H) The short-term and long-term multilineage reconstitution capacities of donor-derived (CD45.1) PB cells in recipients (n = 6; Student’s t test). (I) The percentage of CD45.1+ donor-derived HSCs in the BM of recipients (n = 6; the data represent the means ± SD, Student’s t test). Experiments were conducted 2–3 times for validation. GMP, granulocyte-macrophage progenitor; CMP, common myeloid progenitor; MEP, megakaryocyte-erythrocyte progenitor; CLP, common lymphoid progenitor; MkP, megakaryocyte progenitor.