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Nat Commun. 2014 Sep 12;5:4814. doi: 10.1038/ncomms5814.

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

Author information

1
1] Department of Medicine, School of Medicine, University of California San Diego, La Jolla, California 92093, USA [2] Drug Discovery Center, Key Laboratory of Chemical Genomics, Peking University Shenzhen Graduate School, Shenzhen 518055, China.
2
Skaggs School of Pharmacy, University of California San Diego, La Jolla, California 92093, USA.
3
Department of Cellular and Molecular Medicine, School of Medicine, University of California San Diego, La Jolla, California 92093, USA.
4
Drug Discovery Center, Key Laboratory of Chemical Genomics, Peking University Shenzhen Graduate School, Shenzhen 518055, China.
5
Department of Medicine, School of Medicine, University of California San Diego, La Jolla, California 92093, USA.

Abstract

Calcium ions (Ca(2+)) function as universal second messengers in eukaryotic cells, including immune cells. Ca(2+) is crucial for peripheral T-lymphocyte activation and effector functions, and influences thymocyte selection and motility in the developing thymus. However, the role of Ca(2+) signalling in early T-lymphocyte development is not well understood. Here we show that the inositol triphosphate receptors (IP3Rs) Ca(2+) 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 Ca(2+) 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 Ca(2+) signalling reinforces Tcf-1 activity to both ensure normal development and prevent thymocyte neoplasia.

PMID:
25215520
PMCID:
PMC5537137
DOI:
10.1038/ncomms5814
[Indexed for MEDLINE]
Free PMC Article

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