Inhibitory receptors bind ANGPTLs and support blood stem cells and leukaemia development |
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Authors: | Zheng Junke Umikawa Masato Cui Changhao Li Jiyuan Chen Xiaoli Zhang Chaozheng Huynh HoangDinh Hyunh Hoangdinh Kang Xunlei Silvany Robert Wan Xuan Ye Jingxiao Cantó Alberto Puig Chen Shu-Hsia Wang Huan-You Ward E Sally Zhang Cheng Cheng |
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Affiliation: | Departments of Physiology and Developmental Biology, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA. |
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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. |
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