NOTCH1 Signalling: A key pathway for the development of high-risk chronic lymphocytic leukaemia

Abstract

NOTCH1 is a cell surface receptor that releases its intracellular domain as transcription factor upon activation. With the advent of next-generation sequencing, the NOTCH1 gene was found recurrently mutated in chronic lymphocytic leukaemia (CLL). Here, virtually all NOTCH1 mutations affect the protein’s PEST-domain and impair inactivation and degradation of the released transcription factor, thus increasing NOTCH1 signalling strength. Besides sequence alterations directly affecting the NOTCH1 gene, multiple other genomic and non-genomic alterations have by now been identified in CLL cells that could promote an abnormally strong NOTCH1 signalling strength. This renders NOTCH1 one of the key signalling pathways in CLL pathophysiology. The frequency of genomic alterations affecting NOTCH1 signalling is rising over the CLL disease course culminating in the observation that besides TP53 loss, 8q gain and CDKN2A/B loss, NOTCH1 mutation is a hallmark genomic alteration associated with transformation of CLL into an aggressive lymphoma (Richter transformation). Both findings associate de-regulated NOTCH1 signalling with the development of high-risk CLL. This narrative review provides data on the role of NOTCH1 mutation for CLL development and progression, discusses the impact of NOTCH1 mutation on treatment response, gives insight into potential modes of NOTCH1 pathway activation and regulation, summarises alterations that have been discussed to contribute to a de-regulation of NOTCH1 signalling in CLL cells and provides a perspective on how to assess NOTCH1 signalling in CLL samples.

Expression of Notch1 in Ameloblastoma and Correlation with CBCT Imaging Subtypes

“…This research exclusively employed immunohistochemical techniques to scrutinize theNotch1 protein expression in AM at the protein level. The investigation revealed an up-regulation of Notch1 protein expression in AM, mirroring observations in various other malignancies [24][25][26]. Nevertheless, elucidating the precise mechanistic involvement of the Notch signaling pathway in AM necessitates substantiation through further comprehensive studies at the gene and cellular strata.…”

Targeting the ZMIZ1-Notch1 signaling axis for the treatment of tongue squamous cell carcinoma

“…Notch1, a member of the Notch family, is closely associated with various types of cancers including breast 8 , leukemia 9 , colorectal 10 , and head and neck squamous cell cancers 11 . Deng et al 12 used TCGA and METABRIC gene expression data to report a positive correlation between elevated Notch1 expression and the incidence of triple-negative breast cancer (TNBC).…”