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

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 (IP(3)Rs) Ca2+ ion channels are required for proliferation, survival and developmental progression of T-lymphocyte precursors. Our studies indicate that signalling via IP(3)Rs 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 beta-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.