Notch Signaling Promotes Mature T-Cell Lymphomagenesis

Abstract

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-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 utilized 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.

Bioinformatics identification of a T‐cell‐related signature for predicting prognosis and drug sensitivity in hepatocellular carcinoma

“…Moreover, targeted hypoxia reduction restores T‐cell infiltration and sensitises prostate cancer to immunotherapy [ 51 ]. Notch signalling pathway plays a vital role in mature T‐cell lymphomagenesis [ 52 ].…”

PTCL, NOS: An update on classification, risk-stratification, and treatment

“…Conversely, receptors (e.g. Notch) that are rarely subject to mutations or copy number alterations in mature T-cell lymphomas (in contrast to T-ALL) ( 42 , 65 ), remain dependent upon ligand- and TME-dependent signaling ( 66 ). Finally, the signaling cascades triggered by exogenous and TME-dependent factors, and those activated by gain-of-function genetic alterations, confer sensitivity (or resistance) to novel, targeted agents.…”

“…Furthermore, improved understanding of poorly understood or previously uncharacterized drivers may lead to further additions to, or refinements of, our current understanding of T-cell lymphomagenesis and unveil novel therapeutic targets. For example, ligand-dependent Notch signaling was recently discovered as an important driver of proliferation in PTCL, NOS ( 66 ).…”

Emerging predictive biomarkers for novel therapeutics in peripheral T-cell and natural killer/T-cell lymphoma

“…Mutations in various signaling pathways such as T cell receptors, PTEN-PI3K, NOTCH1 signaling and ITK-SYK have been postulated as progenitors of this oncogenic signaling cascade ( 38 , 40 , 41 ). The NF-κB pathway has also been implicated in cases of PTCL-NOS via identification of signals such as FYN-TRAF3IP2 ( 42 ).…”