Inhibitory receptors bind ANGPTLs and support blood stem cells and leukaemia development

Junke Zheng, Masato Umikawa, Changhao Cui, Jiyuan Li, Xiaoli Chen, Chaozheng Zhang, Hoangdinh Hyunh, Xunlei Kang, Robert Silvany, Xuan Wan, Jingxiao Ye, Alberto Puig Cantó, Shu Hsia Chen, Huan You Wang, E. Sally Ward, Chengcheng Zhang

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Abstract

How environmental cues regulate adult stem cell and cancer cell activity through surface receptors is poorly understood. Angiopoietin-like proteins (ANGPTLs), a family of seven secreted glycoproteins, are known to support the activity of haematopoietic stem cells (HSCs) in vitro and in vivo. ANGPTLs also have important roles in lipid metabolism, angiogenesis and inflammation, but were considered 'orphan ligands' because no receptors were identified. Here we show that the immune-inhibitory receptor human leukocyte immunoglobulin-like receptor B2 (LILRB2) and its mouse orthologue paired immunoglobulin-like receptor (PIRB) are receptors for several ANGPTLs. LILRB2 and PIRB are expressed on human and mouse HSCs, respectively, and the binding of ANGPTLs to these receptors supported ex vivo expansion of HSCs. In mouse transplantation acute myeloid leukaemia models, a deficiency in intracellular signalling of PIRB resulted in increased differentiation of leukaemia cells, revealing that PIRB supports leukaemia development. Our study indicates an unexpected functional significance of classical immune-inhibitory receptors in maintenance of stemness of normal adult stem cells and in support of cancer development.

Original languageEnglish (US)
Pages (from-to)656-660
Number of pages5
JournalNature
Volume485
Issue number7400
DOIs
StatePublished - Jan 1 2012

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Zheng, J., Umikawa, M., Cui, C., Li, J., Chen, X., Zhang, C., Hyunh, H., Kang, X., Silvany, R., Wan, X., Ye, J., Cantó, A. P., Chen, S. H., Wang, H. Y., Ward, E. S., & Zhang, C. (2012). Inhibitory receptors bind ANGPTLs and support blood stem cells and leukaemia development. Nature, 485(7400), 656-660. https://doi.org/10.1038/nature11095