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

Kunfu Ouyang, Rafael Leandro Gomez-Amaro, David L. Stachura, Huayuan Tang, Xiaohong Peng, Xi Fang, David Traver, Sylvia M. Evans () and Ju Chen ()
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Kunfu Ouyang: School of Medicine, University of California San Diego
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

Nature Communications, 2014, vol. 5, issue 1, 1-12

Abstract: 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.

Date: 2014
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DOI: 10.1038/ncomms5814

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