The Predominant Prognostic Significance of NOTCH1 Mutation Defined by Emulsion PCR in Chronic Lymphocytic Leukemia

Skórka, Katarzyna; Chojnacki, Michał; Masternak, Marta; Karczmarczyk, Agnieszka; Subocz, Edyta; Wawrzyniak, Ewa; Giannopoulos, Krzysztof

doi:10.2147/cmar.s302245

Cited by 2 publications

(1 citation statement)

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“…Overall, the incidence of these mutations varies at different disease stages, ranging from about 3–11% at the MBL stage [ 121 , 122 ], to 15–25% at CLL diagnosis [ 10 , 11 ], and 20–40% for refractory/relapsed CLL and Richter syndrome [ 12 , 13 ]. In addition, the average mutational burden can vary greatly, has evolved over time in parallel with technological advancements such as NGS [ 10 , 11 ] and droplet digital PCR [ 123 , 124 , 125 ]. In particular, the latter studies report a detection limit of 0.03% for variant allele frequency, way lower than the NGS limit of about 0.3–1.3 [ 11 , 126 ]; in parallel, they have also suggested that NOTCH1 delCT mutations may be present in a greater fraction of CLL cells, ranging from 18.6–25% [ 124 , 125 ] up to 55% in CLL cases with trisomy 12.…”

Section: Notch1 Mutations In Cllmentioning

confidence: 99%

Multiple Mechanisms of NOTCH1 Activation in Chronic Lymphocytic Leukemia: NOTCH1 Mutations and Beyond

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et al. 2022

Cancers

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The Notch signaling pathway plays a fundamental role for the terminal differentiation of multiple cell types, including B and T lymphocytes. The Notch receptors are transmembrane proteins that, upon ligand engagement, undergo multiple processing steps that ultimately release their intracytoplasmic portion. The activated protein ultimately operates as a nuclear transcriptional co-factor, whose stability is finely regulated. The Notch pathway has gained growing attention in chronic lymphocytic leukemia (CLL) because of the high rate of somatic mutations of the NOTCH1 gene. In CLL, NOTCH1 mutations represent a validated prognostic marker and a potential predictive marker for anti-CD20-based therapies, as pathological alterations of the Notch pathway can provide significant growth and survival advantage to neoplastic clone. However, beside NOTCH1 mutation, other events have been demonstrated to perturb the Notch pathway, namely somatic mutations of upstream, or even apparently unrelated, proteins such as FBXW7, MED12, SPEN, SF3B1, as well as physiological signals from other pathways such as the B-cell receptor. Here we review these mechanisms of activation of the NOTCH1 pathway in the context of CLL; the resulting picture highlights how multiple different mechanisms, that might occur under specific genomic, phenotypic and microenvironmental contexts, ultimately result in the same search for proliferative and survival advantages (through activation of MYC), as well as immune escape and therapy evasion (from anti-CD20 biological therapies). Understanding the preferential strategies through which CLL cells hijack NOTCH1 signaling may present important clues for designing targeted treatment strategies for the management of CLL.

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