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Loss of IP3R-dependent Ca2+ signalling in thymocytes leads to aberrant development and acute lymphoblastic leukemia

Author

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  • Kunfu Ouyang

    (School of Medicine, University of California San Diego
    Drug Discovery Center, Key Laboratory of Chemical Genomics, Peking University Shenzhen Graduate School)

  • Rafael Leandro Gomez-Amaro

    (Skaggs School of Pharmacy, University of California San Diego)

  • David L. Stachura

    (School of Medicine, University of California San Diego)

  • Huayuan Tang

    (Drug Discovery Center, Key Laboratory of Chemical Genomics, Peking University Shenzhen Graduate School)

  • Xiaohong Peng

    (Drug Discovery Center, Key Laboratory of Chemical Genomics, Peking University Shenzhen Graduate School)

  • Xi Fang

    (School of Medicine, University of California San Diego)

  • David Traver

    (School of Medicine, University of California San Diego)

  • Sylvia M. Evans

    (Skaggs School of Pharmacy, University of California San Diego)

  • Ju Chen

    (School of Medicine, University of California San Diego)

Abstract

Calcium ions (Ca2+) function as universal second messengers in eukaryotic cells, including immune cells. Ca2+ is crucial for peripheral T-lymphocyte activation and effector functions, and influences thymocyte selection and motility in the developing thymus. However, the role of Ca2+ signalling in early T-lymphocyte development is not well understood. Here we show that the inositol triphosphate receptors (IP3Rs) Ca2+ ion channels are required for proliferation, survival and developmental progression of T-lymphocyte precursors. Our studies indicate that signalling via IP3Rs represses Sox13, an antagonist of the developmentally important transcription factor Tcf-1. In the absence of IP3R-mediated Ca2+ signalling, repression of key Notch transcriptional targets—including Hes1—fail to occur in post β-selection thymocytes, and mice develop aggressive T-cell malignancies that resemble human T-cell acute lymphoblastic leukemia (T-ALL). These data indicate that IP3R-mediated Ca2+ signalling reinforces Tcf-1 activity to both ensure normal development and prevent thymocyte neoplasia.

Suggested Citation

  • Kunfu Ouyang & Rafael Leandro Gomez-Amaro & David L. Stachura & Huayuan Tang & Xiaohong Peng & Xi Fang & David Traver & Sylvia M. Evans & Ju Chen, 2014. "Loss of IP3R-dependent Ca2+ signalling in thymocytes leads to aberrant development and acute lymphoblastic leukemia," Nature Communications, Nature, vol. 5(1), pages 1-12, December.
    • Handle: RePEc:nat:natcom:v:5:y:2014:i:1:d:10.1038_ncomms5814
    DOI: 10.1038/ncomms5814
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    Cited by:

    1. Meng Xu & Taku Ito-Kureha & Hyun-Seo Kang & Aleksandar Chernev & Timsse Raj & Kai P. Hoefig & Christine Hohn & Florian Giesert & Yinhu Wang & Wenliang Pan & Natalia Ziętara & Tobias Straub & Regina Fe, 2024. "The thymocyte-specific RNA-binding protein Arpp21 provides TCR repertoire diversity by binding to the 3’-UTR and promoting Rag1 mRNA expression," Nature Communications, Nature, vol. 15(1), pages 1-20, December.

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