Role of Notch Receptors in Hematologic Malignancies

Abstract

Notch receptors are single-pass transmembrane proteins that play a critical role in cell fate decisions and have been implicated in the regulation of many developmental processes. The human Notch family comprises of four receptors (Notch 1 to 4) and five ligands. Their signaling can regulate extremely basic cellular processes such as differentiation, proliferation and death. Notch is also involved in hematopoiesis and angiogenesis, and increasing evidence suggests that these genes are involved and frequently deregulated in several human malignancies, contributing to cell autonomous activities that may be either oncogenic or tumor suppressive. It was recently proposed that Notch signaling could play an active role in promoting and sustaining a broad spectrum of lymphoid malignancies as well as mutations in Notch family members that are present in several disorders of T- and B-cells, which could be responsible for altering the related signaling. Therefore, different Notch pathway molecules could be considered as potential therapeutic targets for hematological cancers. In this review, we will summarize and discuss compelling evidence pointing to Notch receptors as pleiotropic regulators of hematologic malignancies biology, first describing the physiological role of their signaling in T- and B-cell development and homeostasis, in order to fully understand the pathological alterations reported.

Identification and Assessment of Necroptosis-Related Genes in Clinical Prognosis and Immune Cells in Diffuse Large B-Cell Lymphoma

“…KEGG pathway analysis showed that the highly expressed genes in cluster A with poor prognosis were mainly enriched in the Notch signaling pathway, while the lowly expressed genes were enriched in the TGF-β signaling pathway. Notch plays a role in promoting and maintaining lymphoid malignancies by regulating relevant signaling pathways ( 50 ). The Notch signaling pathway has been reported to be aberrantly activated in DLBCL ( 51 ), and it has also been found that Notch can interact with the tumor or stem cell microenvironment via stromal cells ( 52 ).…”

Roles of Notch Signaling in the Tumor Microenvironment

“…There is accumulating evidence that Notch signaling plays a role in tuning the immune responses in tumors, which is in line with Notch signaling playing a pivotal role in normal hematopoiesis and in generation of various types of immune effector cells [ 94 ]. Notably, Notch signaling is a key regulator of the choice between the B- and T-cell lineages and subsequently regulates the specification of various T-cell subclasses [ 95 ]. Notch signaling also plays a role in inflammatory processes, for example by exacerbating the T-cell response in the experimental autoimmune encephalomyelitis (EAE) mouse model for multiple sclerosis [ 96 , 97 , 98 ].…”

The Role of Notch, Hedgehog, and Wnt Signaling Pathways in the Resistance of Tumors to Anticancer Therapies

“…Later, its role in other hematological malignancies such as B-cell chronic lymphocytic leukemia (B-CLL) (Rosati et al, 2009), mantle cells lymphoma (MCL), Multiple Myeloma, AML, etc. has been well established (Gragnani et al, 2020). Recently, a genome-wide study in relapse cases of T-cell lymphoblastic lymphoma (T-LBL) identified Notch1 as the putative driver for relapse and malignancy (Khanam et al, 2020).…”