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

Patel, Varsha M.; Flanagan, Charlotte E.; Martins, Marta; Jones, Christine L.; Butler, Rosie M.; Woollard, Wesley J.; Bakr, Farrah; Yoxall, Antoinette; Begum, Nelema; Katan, Matilda; Whittaker, Sean; Mitchell, Tracey

doi:10.1016/j.jid.2019.07.693

Cited by 28 publications

(27 citation statements)

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“…The major, comprehensive discoveries are described in a number of publications [215][216][217][218][219][220][221][222][223][224]. Interestingly, in a number of cases where functional characterization of the effect of genetic changes on PLC activity has been performed, these alterations (predominantly single aminoacid substitutions) result in an increase of PLC activity under basal and/or stimulated conditions [83,84,215,217,219,[225][226][227][228]. Consequently, terms "gain-of-function mutation" (a mutation that confers new or enhanced activity on a protein) and "hypermorphic mutation" (mutation in which the altered gene product possesses an increased level of activity) have been used when describing these PLC variants.…”

Section: Plcβ4mentioning

confidence: 99%

“…Subsequently, PLCG1 mutations were discovered in another type of rare malignancies, T-cell lymphomas, including cutaneous T-cell lymphoma (CTCL) and adult T-cell leukaemia/lymphoma (ATLL or ATL; linked to a human T-lymphotropic virus type 1/HTLV-1) [222,228,[243][244][245][246][247][248][249][250][251][252][253][254][255][256][257][258][259][260]. In ATL, PLCG1 is the most frequently mutated gene (36%, based on the largest study [222]) and, as in other T-cell lymphomas, have been linked to the aberrant TCR signal transduction pathway.…”

Section: J O U R N a L P R E -P R O O Fmentioning

confidence: 99%

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Phospholipase C families: Common themes and versatility in physiology and pathology

Katan

Cockcroft

2020

Progress in Lipid Research

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This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

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Section: Plcβ4mentioning

confidence: 99%

Section: J O U R N a L P R E -P R O O Fmentioning

confidence: 99%

Phospholipase C families: Common themes and versatility in physiology and pathology

Katan

Cockcroft

2020

Progress in Lipid Research

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“…It was shown previously that mutated PLCG1 increases the survival signaling via NF-kB, NFAT and AP-1. 11,44 Mutated STAT3 was also shown to have a pathogenic role in CTCL. 45,46 .…”

Section: Discussionmentioning

confidence: 99%

Transcriptomic Changes During Stage Progression of Mycosis Fungoides

Xiao

Hennessey

Iyer

et al. 2021

Preprint

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Background: Mycosis fungoides (MF) is the most common cutaneous T cell lymphoma, which in the early patch/plaque stages runs an indolent course. However, ~25% of MF patients develop skin tumors, a hallmark of progression to the advanced stage and associated with high mortality. The mechanisms involved in stage progression are poorly elucidated. Methods: We performed whole-transcriptome and whole-exome sequencing of malignant MF cells from skin biopsies obtained by laser-capture microdissection. We compared three types of MF lesions: early-stage plaques (ESP, n=12), and plaques and tumors from patients in late-stage disease (late-stage plaques, LSP, n=10, and tumors, TMR, n=15). Gene Ontology (GO) and KEGG analysis were used to determine pathway changes specific for different lesions which we linked to the recurrent somatic mutations overrepresented in MF tumors. Results: The key upregulated pathways during stage progression were those related to cell proliferation and survival (MEK/ERK, Akt-mTOR), Th2/Th9 signaling (IL4, STAT3, STAT5, STAT6), meiomitosis (CT45A1, CT45A3, STAG3, GTSF1, and REC8) and DNA repair (PARP1, MYCN, OGG1). Principal coordinate clustering of the transcriptome revealed extensive gene expression differences between early (ESP) and advanced-stage lesions (LSP and TMR). LSP and TMR showed remarkable similarities at the level of the transcriptome, which we interpreted as evidence of cell percolation between lesions via hematogenous self-seeding. Conclusion: Stage progression in MF is associated with Th2/Th9 polarization of malignant cells, activation of proliferation, survival, as well as increased genomic instability. Global transcriptomic changes in multiple lesions are probably caused by hematogenous cell percolation between discrete skin lesions.

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“…In the present study, curcumin downregulated ALK, as well as the phosphorylated form of one of the downstream effectors of ALK, PLCγ, which may serve an important role in the progression of the disease. Bona fide gain of function mutations of PLCγ1, the PLCγ form predominantly expressed by T cells ( 86 ), lead to the constitutive activation of proximal and distal PLCγ1 signaling cascades, including the activation of NF-κB, with the inhibition of this pathway resulting in decreased CTCL cell proliferation and viability ( 87 – 89 ).…”

Section: Discussionmentioning

confidence: 99%

Antineoplastic effect of a novel nanosized curcumin on cutaneous T cell lymphoma

et al. 2020

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Cutaneous T cell lymphomas (CTCLs) are a group of heterogeneous, life-threatening, extra-nodal and lymphoproliferative T cell neoplasms. Since chronic inflammation serves a key role in CTCL progression, curcumin, a natural pigment with proven anti-inflammatory and antineoplastic properties, as well as minimal toxicity, may be used as a therapeutic agent. In the present study, two formulations of curcumin (standard ethanolic and a Pluronic ® P-123/F-127 micellar solution) were compared regarding their cytotoxic efficacy and speed of internalization in three CTCL cell lines, namely HuT-78, HH and MJ. In addition, the modulating effect of curcumin on selected proteins involved in the proliferation and progression of the disease was determined. The results indicated the superiority of the Pluronic ® P-123/F-127 micellar curcumin over the standard ethanol solution in terms of cellular internalization efficiency as determined by spectrophotometric analysis. Notably, the presence of commonly used media components, such as phenol red, may interfere when interpreting the cytotoxicity of curcumin, due to their overlapping absorbance peaks. Therefore, it was concluded that phenol red-free media are superior over media with phenol red in order to correctly measure the cytotoxic efficacy and cell penetration of curcumin. Depending on the cell line, the IC 50 values of micellar curcumin varied from 29.76 to 1.24 µΜ, with HH cells demonstrating the highest sensitivity. This cell line had the lowest expression levels of the Wilms' tumor-1 transcription factor. Performing western blot analyses of treated and untreated CTCL cells, selective signal transduction changes were recorded for the first time, thus making curcumin nano-formulation an attractive and prospective option with therapeutic relevance for CTCL as a rare orphan disease.

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

Cited by 28 publications

References 57 publications

Phospholipase C families: Common themes and versatility in physiology and pathology

Phospholipase C families: Common themes and versatility in physiology and pathology

Transcriptomic Changes During Stage Progression of Mycosis Fungoides

Antineoplastic effect of a novel nanosized curcumin on cutaneous T cell lymphoma

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

Cited by 28 publications

References 57 publications

Phospholipase C families: Common themes and versatility in physiology and pathology

Phospholipase C families: Common themes and versatility in physiology and pathology

Transcriptomic Changes During Stage Progression of Mycosis Fungoides

Antineoplastic effect of a novel nanosized curcumin on cutaneous T&nbsp;cell lymphoma

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Antineoplastic effect of a novel nanosized curcumin on cutaneous T cell lymphoma