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Frequent and Persistent PLCG1 Mutations in Sezary Cells Directly Enhance PLC gamma 1 Activity and Stimulate NF kappa B, AP-1, and NFAT Signaling

Patel, VM; Flanagan, CE; Martins, M; Jones, CL; Butler, RM; Woollard, WJ; Bakr, FS; ... Mitchell, TJ; + view all (2020) Frequent and Persistent PLCG1 Mutations in Sezary Cells Directly Enhance PLC gamma 1 Activity and Stimulate NF kappa B, AP-1, and NFAT Signaling. Journal of Investigative Dermatology , 140 (2) pp. 380-389. 10.1016/j.jid.2019.07.693. Green open access

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Abstract

Phospholipase C Gamma 1 (PLCG1) is frequently mutated in primary cutaneous T-cell lymphoma (CTCL). This study functionally interrogated nine PLCG1 mutations (p.R48W, p.S312L, p.D342N, p.S345F, p.S520F, p.R1158H, p.E1163K, p.D1165H, and the in-frame indel p.VYEEDM1161V) identified in Sézary Syndrome, the leukemic variant of CTCL. The mutations were demonstrated in diagnostic samples and persisted in multiple tumor compartments over time, except in patients who achieved a complete clinical remission. In basal conditions, the majority of the mutations confer PLCγ1 gain-of-function activity through increased inositol phosphate production and the downstream activation of NFκB, AP-1, and NFAT transcriptional activity. Phosphorylation of the p.Y783 residue is essential for the proximal activity of wild-type PLCγ1, but we provide evidence that activating mutations do not require p.Y783 phosphorylation to stimulate downstream NFκB, NFAT, and AP-1 transcriptional activity. Finally, the gain-of-function effects associated with the p.VYEEDM1161V indel suggest that the C2 domain may have a role in regulating PLCγ1 activity. These data provide compelling evidence to support the development of therapeutic strategies targeting mutant PLCγ1.

Type: Article
Title: Frequent and Persistent PLCG1 Mutations in Sezary Cells Directly Enhance PLC gamma 1 Activity and Stimulate NF kappa B, AP-1, and NFAT Signaling
Open access status: An open access version is available from UCL Discovery
DOI: 10.1016/j.jid.2019.07.693
Publisher version: https://doi.org/10.1016/j.jid.2019.07.693
Language: English
Additional information: This version is the author accepted manuscript. For information on re-use, please refer to the publisher’s terms and conditions.
Keywords: Science & Technology, Life Sciences & Biomedicine, Dermatology, PHOSPHOLIPASE C-GAMMA, CHRONIC LYMPHOCYTIC-LEUKEMIA, TUMOR-NECROSIS-FACTOR, CONSTITUTIVE ACTIVATION, MYCOSIS-FUNGOIDES, GENE-MUTATIONS, RESISTANCE, LYMPHOMA, LANDSCAPE, RHOA
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences > Structural and Molecular Biology
URI: https://discovery.ucl.ac.uk/id/eprint/10091928
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