c‐Myc‐Induced Survivin Is Essential for Promoting  the Notch‐Dependent T Cell Differentiation from  Hematopoietic Stem Cells

Abstract

Notch is indispensable for T cell lineage commitment, and is needed for thymocyte differentiation at early phases. During early stages of T cell development, active Notch prevents other lineage potentials including B cell lineage and myeloid cell (e.g., dendritic cell) lineage. Nevertheless, the precise intracellular signaling pathways by which Notch promotes T cell differentiation remain unclear. Here we report that the transcription factor c‐Myc is a key mediator of the Notch signaling–regulated T cell differentiation. In a well‐established in vitro differentiation model of T lymphocytes from hematopoietic stem cells, we showed that Notch1 and 4 directly promoted c‐Myc expression; dominant‐negative (DN) c‐Myc inhibited early T cell differentiation. Moreover, the c‐Myc expression activated by Notch signaling increased the expression of survivin, an inhibitor of apoptosis (IAP) protein. We further demonstrated that over‐expression of c‐Myc increased the abundance of survivin and the T cell differentiation thereof, whereas dn c‐Myc reduced survivin levels and concomitantly retarded the differentiation. The c‐Myc–dependent survivin induction is functionally germane, because Notch‐dependent T cell differentiation was canceled by the depletion of survivin. These results identify both c‐Myc and survivin as important mediators of the Notch signaling–regulated differentiation of T lymphocytes from hematopoietic stem cells.

Keywords

• Notch signaling
•  c‐Myc
•  hematopoietic stem cells
•  T cells
•  cell differentiation