Article | Published:

The ITIM-containing receptor LAIR1 is essential for acute myeloid leukaemia development

Nature Cell Biology volume 17, pages 665677 (2015) | Download Citation

Abstract

Conventional strategies are not particularly successful in the treatment of leukaemia, and identification of signalling pathways crucial to the activity of leukaemia stem cells will provide targets for the development of new therapies. Here we report that certain receptors containing the immunoreceptor tyrosine-based inhibition motif (ITIM) are crucial for the development of acute myeloid leukaemia (AML). Inhibition of expression of the ITIM-containing receptor LAIR1 does not affect normal haematopoiesis but abolishes leukaemia development. LAIR1 induces activation of SHP-1, which acts as a phosphatase-independent signalling adaptor to recruit CAMK1 for activation of downstream CREB in AML cells. The LAIR1–SHP-1–CAMK1–CREB pathway sustains the survival and self-renewal of AML stem cells. Intervention in the signalling initiated by ITIM-containing receptors such as LAIR1 may result in successful treatment of AML.

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Acknowledgements

We would like to thank H. Saya from Keio University School of Medicine for the pMX-IG N-Myc vector. We appreciate the support of staff of the tissue bank at the Department of Hematopathology, the University of Texas MD Anderson Cancer Center. Support to C.C.Z. was from NIH grant 1R01CA172268, Leukemia & Lymphoma Society Awards 1024-14 and TRP-6024-14, CPRIT RP140402, March of Dimes Foundation grant 1-FY14-201, Robert A. Welch Foundation grant I-1834, and When Everyone Survives Foundation. J.W.T. is supported by grants from the V Foundation for Cancer Research, the William Lawrence and Blanche Hughes Fund, and the National Cancer Institute (4 R00CA151457-03), and the Leukemia & Lymphoma Society. X.X. is supported by Susan G. Komen Foundation and RO1GM087305. J.E.C. is supported by the intramural program of the National Institute of Allergy and Infectious Diseases. M.J.Y. is supported in part by NIH/NCI R01 CA164346, Ladies Leukemia League, Developmental Research Awards in Leukemia SPORE CA100632, and Center for Inflammation and Cancer, IRG, Center for Genetics and Genomics, Sister Institution Network Fund and Physician Scientist Award of the University of Texas MD Anderson Cancer Center.

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Affiliations

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

    • Xunlei Kang
    • , Zhigang Lu
    • , Changhao Cui
    • , Mi Deng
    • , Yuqi Fan
    •  & Cheng Cheng Zhang
  2. Department of Hematopathology, Division of Pathology and Laboratory Medicine, University of Texas MD Anderson Cancer Center, Houston, Texas 77030-4009, USA

    • Baijun Dong
    •  & M. James You
  3. Department of Laboratory Medicine, Division of Pathology and Laboratory Medicine, University of Texas MD Anderson Cancer Center, Houston, Texas 77030-4009, USA

    • Xin Han
  4. Department of Physiology and Pharmacology, Oregon Health and Science University Knight Cancer Institute, Portland, Oregon 97239, USA

    • Fuchun Xie
    •  & Xiangshu Xiao
  5. Cell and Developmental Biology, Oregon Health and Science University Knight Cancer Institute, Portland, Oregon 97239, USA

    • Jeffrey W. Tyner
  6. Receptor Cell Biology Section, National Institute of Allergy and Infectious Diseases, NIH, Rockville, Maryland 20852, USA

    • John E. Coligan
  7. Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA

    • Robert H. Collins
  8. The University of Texas Graduate School of Biomedical Sciences at Houston, Houston, Texas 77030, USA

    • M. James You
  9. School of Life Science and Medicine, Dalian University of Technology, Panjin, Liaoning 124221, China

    • Changhao Cui

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Contributions

X.K. performed most of the experiments, analysed data and contributed to writing the paper; Z.L. performed the TCGA and clustering analyses; C.C. performed the CAMK experiments; M.D. performed the LILRB knockdown experiments. Y.F., F.X. and X.X. performed the CREB inhibitor experiments and provided advice; B.D., X.H., R.H.C. and M.J.Y. collected the primary AML samples and provided advice; J.W.T. helped with experiments using leukaemia cell lines and contributed to paper writing; J.E.C. provided LAIR1-deficient mice and contributed to paper writing; C.C.Z. conceived, coordinated and supervised the project, designed experiments, analysed data and wrote the paper.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Cheng Cheng Zhang.

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DOI

https://doi.org/10.1038/ncb3158

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