Frequent and Persistent PLCG1 Mutations in Sézary Cells Directly Enhance PLCγ1 Activity and Stimulate NFκB, AP-1, and NFAT Signaling

The Journal of Investigative Dermatology
Varsha M PatelTracey J Mitchell

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.

References

Jan 1, 1994·Applied and Environmental Microbiology·F J van KuppeveldW J Melchers
Sep 17, 2003·Genes & Development·Patrick G HoganAnjana Rao
Jun 25, 2004·Nucleic Acids Research·Stephen R ComeauCarlos J Camacho
Mar 15, 2005·Proceedings of the National Academy of Sciences of the United States of America·Benoit PoulinSue Goo Rhee
Apr 21, 2005·The Journal of Clinical Investigation·Ellen J KimAlain H Rook
Jan 10, 2009·Annual Review of Immunology·Jennifer E Smith-GarvinMartha S Jordan
Jun 18, 2009·The Journal of Biological Chemistry·Katy L EverettMatilda Katan
Sep 3, 2010·The Journal of Biological Chemistry·Aurelie GressetJohn Sondek
Jan 27, 2011·The Journal of Biological Chemistry·Ryan R KleinDhiren R Thakker
Oct 13, 2011·Molecular Systems Biology·Fabian SieversDesmond G Higgins
Jan 13, 2012·The New England Journal of Medicine·Michael J OmbrelloJoshua D Milner
Oct 13, 2012·Frontiers in Microbiology·Makoto Yamagishi, Toshiki Watanabe
Jan 15, 2014·Nature Genetics·Mamiko Sakata-YanagimotoShigeru Chiba
Jan 21, 2014·The Journal of Dermatology·Tomomitsu Miyagaki, Makoto Sugaya
Feb 6, 2014·Blood·José P VaquéMargarita Sánchez-Beato
Apr 1, 2014·Nature Methods·Jana Marie SchwarzDominik Seelow
Dec 3, 2014·Trends in Biochemical Sciences·Hans KossMatilda Katan
Apr 25, 2015·The Journal of Investigative Dermatology·Charline CaumontDavid Cappellen
Jun 18, 2015·Blood·Laura Y McGirtChristine M Eischen
Jul 21, 2015·Nature Genetics·Jaehyuk ChoiRichard P Lifton
Oct 6, 2015·Nature Genetics·Keisuke KataokaSeishi Ogawa
Nov 10, 2015·Nature Genetics·Ana Carolina da Silva AlmeidaTeresa Palomero
Apr 4, 2016·The Journal of Investigative Dermatology·Aparna PrasadXavier Estivill
Jan 27, 2017·Cancer Discovery·Matthew McKinneySandeep S Davé

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Citations

Sep 24, 2020·Progress in Lipid Research·Matilda Katan, Shamshad Cockcroft
Oct 24, 2021·The Journal of Investigative Dermatology·N García-DíazJ P Vaqué
Sep 17, 2021·The British Journal of Dermatology·M Z X XiaoR Gniadecki

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