{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,30]],"date-time":"2026-04-30T01:31:24Z","timestamp":1777512684181,"version":"3.51.4"},"reference-count":73,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,10,13]],"date-time":"2022-10-13T00:00:00Z","timestamp":1665619200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Oncol."],"abstract":"<jats:p>NOTCH1 is a cell surface receptor that releases its intracellular domain as transcription factor upon activation. With the advent of next-generation sequencing, the <jats:italic>NOTCH1<\/jats:italic> gene was found recurrently mutated in chronic lymphocytic leukaemia (CLL). Here, virtually all <jats:italic>NOTCH1<\/jats:italic> mutations affect the protein\u2019s PEST-domain and impair inactivation and degradation of the released transcription factor, thus increasing NOTCH1 signalling strength. Besides sequence alterations directly affecting the <jats:italic>NOTCH1<\/jats:italic> 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 <jats:italic>TP53<\/jats:italic> loss, 8q gain and <jats:italic>CDKN2A<\/jats:italic>\/<jats:italic>B<\/jats:italic> loss, <jats:italic>NOTCH1<\/jats:italic> 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 <jats:italic>NOTCH1<\/jats:italic> mutation for CLL development and progression, discusses the impact of <jats:italic>NOTCH1<\/jats:italic> 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.<\/jats:p>","DOI":"10.3389\/fonc.2022.1019730","type":"journal-article","created":{"date-parts":[[2022,10,13]],"date-time":"2022-10-13T08:33:46Z","timestamp":1665650026000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":6,"title":["NOTCH1 Signalling: A key pathway for the development of high-risk chronic lymphocytic 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