Notch Signaling Promotes Mature T-Cell Lymphomagenesis

Abstract

Peripheral T-cell lymphomas (PTCL) are agressive lymphomas engineered mouse models and spontaneous PTCL models were that develop from mature T cells. The most common PTCLs are used to functionally examine the role of Notch signaling, and genetically, molecularly, and clinically diverse and are generally Notch1/Notch2 blockade and pan-Notch blockade using domiassociated with dismal outcomes. While Notch signaling plays a nant-negative MAML significantly impaired the proliferation of critically important role in both the development of immature T malignant T cells and PTCL progression in these models. Treatment cells and their malignant transformation, its role in PTCL is poorly with DLL1/DLL4 blocking antibodies established that Notch sigunderstood, despite the increasingly appreciated function of Notch naling is ligand-dependent. Together, these findings reveal a role for in regulating the proliferation and differentiation of mature T cells. ligand-dependent Notch signaling in driving peripheral T-cell Here, we demonstrate that Notch receptors and their Delta-like lymphomagenesis. family ligands (DLL1/DLL4) play a pathogenic role in PTCL. Notch1 activation was observed in common PTCL subtypes, includSignificance: This work demonstrates that ligand-dependent ing PTCL-not otherwise specified (NOS). In a large cohort of PTCL-Notch activation promotes the growth and proliferation of mature NOS biopsies, Notch1 activation was significantly associated with T-cell lymphomas, providing new therapeutic strategies for this surrogate markers of proliferation. Complementary genetically group of aggressive lymphomas.