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

Nature volume 485, pages 656–660 (2012)Cite this article

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A Corrigendum to this article was published on 04 July 2012

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 vivo1,2,3,4,5,6,7,8,9,10. ANGPTLs also have important roles in lipid metabolism, angiogenesis and inflammation, but were considered ‘orphan ligands’ because no receptors were identified3,11,12. 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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Figure 1: Cell-surface LILRB2 binds to ANGPTLs.
Figure 2: LILRB2 mediates the effect of ANGPTL in supporting the repopulation of human cord blood HSCs.
Figure 3: ANGPTLs bind PIRB and support the repopulation of mouse HSCs.
Figure 4: PIRB suppresses differentiation and enhances development of MLL–AF9 AML.

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Gene Expression Omnibus

Data deposits

DNA microarray data are available for download from the GEO under accession number GSE36329.

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Acknowledgements

We thank S. Armstrong for the MSCV–MLL–AF9–IRES–YFP construct, H. Hobbs for the CMV–ANGPTL6–Flag plasmid, T. Takai for providing the PIRB knockout mice to S.-H.C., X.-J. Xie for binding analysis, and UTSW Genomics and Microarray Core facility for DNA array experiments. S.-H.C. thanks support from NIH. C.C.Z. was supported by NIH grant K01 CA 120099, American Society of Hematology Junior Faculty Award, March of Dimes Basil O’Connor Scholar Award, DOD PR093256, CPRIT RP100402, and the Gabrielle’s Angel Foundation.

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Author notes

  1. Junke Zheng, Masato Umikawa and Changhao Cui: These authors contributed equally to this work.

Authors and Affiliations

  1. Departments of Physiology and Developmental Biology, University of Texas Southwestern Medical Center, Dallas, 75390, Texas, USA

    Junke Zheng, Masato Umikawa, Changhao Cui, Jiyuan Li, Xiaoli Chen, Chaozheng Zhang, HoangDinh Huynh, Xunlei Kang, Robert Silvany, Xuan Wan, Jingxiao Ye & Cheng Cheng Zhang

  2. Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China

    Junke Zheng

  3. Department of Medical Biochemistry, University of the Ryukyus, Okinawa 903-0215, Japan,

    Masato Umikawa

  4. Department of Immunology, University of Texas Southwestern Medical Center, Dallas, 75390, Texas, USA

    Alberto Puig Cantó & E. Sally Ward

  5. Department of Oncological Sciences, Mount Sinai School of Medicine, New York, 10029-6574, New York, USA

    Shu-Hsia Chen

  6. Department of Pathology, University of California San Diego, La Jolla, 92093, California, USA

    Huan-You Wang

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Contributions

J.Z., M.U., C.C. and C.C.Z. were responsible for the study design, identification of receptors, binding, signalling and functional assays, data analysis and writing of the manuscript. J.L., X.C., C.Z., H.H., X.K., R.S. and X.W. were responsible for binding and signalling assays and data analysis. J.Y. and S.-H.C. carried out the ligand-binding assays, H.-Y.W. carried out AML characterization, and A.P.C. and E.S.W. carried out the SPR assay and data analysis.

Corresponding author

Correspondence to Cheng Cheng Zhang.

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Zheng, J., Umikawa, M., Cui, C. et al. Inhibitory receptors bind ANGPTLs and support blood stem cells and leukaemia development. Nature 485, 656–660 (2012). https://doi.org/10.1038/nature11095

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