Notch Signaling Promotes Mature T-Cell Lymphomagenesis

Xin Gao, Chenguang Wang, Suhaib Abdelrahman, Nermin Kady, Carlos Murga-Zamalloa, Peter Gann, Maria Sverdlov, Ashley Wolfe, Avery Polk, Noah Brown, Nathanael G. Bailey, Kedar Inamdar, Sandro Casavilca-Zambrano, Jaime Montes, Carlos Barrionuevo, Luis Taxa, John Reneau, Christian W. Siebel, Ivan Maillard, Ryan A. Wilcox

Resultado de la investigación: Contribución a una revistaArtículorevisión exhaustiva

Resumen

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

Idioma originalInglés
Páginas (desde-hasta)3763-3773
Número de páginas11
PublicaciónCancer Research
Volumen82
N.º20
DOI
EstadoPublicada - 17 oct. 2022
Publicado de forma externa

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Publisher Copyright:
©2022 American Association for Cancer Research.

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