Imperial College London
Alternate

ProfessorCharlesBangham

Institute of Infection

Co-Director of the Institute of Infection
 
 
 
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Contact

 

+44 (0)20 7594 3730c.bangham Website

 
 
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Assistant

 

Ms Linda Hollick +44 (0)20 7594 3729

 
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Location

 

115Wright Fleming WingSt Mary's Campus

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Summary

 

Publications

Citation

BibTex format

@article{Prawiro:2023:10.1016/j.bbadis.2022.166601,
author = {Prawiro, C and Bunney, TD and Kampyli, C and Yaguchi, H and Katan, M and Bangham, CRM},
doi = {10.1016/j.bbadis.2022.166601},
journal = {BBA: Molecular Basis of Disease},
title = {A frequent PLCγ1 mutation in adult T-cell leukemia/lymphoma determines functional properties of the malignant cells},
url = {http://dx.doi.org/10.1016/j.bbadis.2022.166601},
volume = {1869},
year = {2023}
}
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RIS format (EndNote, RefMan)

TY  - JOUR
AB  - BackgroundDevelopment of adult T-cell leukemia/lymphoma (ATL) involves human T-cell leukemia virus type 1 (HTLV-1) infection and accumulation of somatic mutations. The most frequently mutated gene in ATL (36 % of cases) is phospholipase C gamma1 (PLCG1). PLCG1 is also frequently mutated in other T-cell lymphomas. However, the functional consequences of the PLCG1 mutations in cancer cells have not been characterized.MethodsWe compared the activity of the wild-type PLCγ1 with that of a mutant carrying a hot-spot mutation of PLCγ1 (S345F) observed in ATL, both in cells and in cell-free assays. To analyse the impact of the mutation on cellular properties, we quantified cellular proliferation, aggregation, chemotaxis and apoptosis by live cell-imaging in an S345F+ ATL-derived cell line (KK1) and a KK1 cell line in which we reverted the mutation to the wild-type sequence using CRISPR/Cas9 and homology-directed repair.FindingsThe PLCγ1 S345F mutation results in an increase of basal PLC activity in vitro and in different cell types. This higher basal activity is further enhanced by upstream signalling. Reversion of the S345F mutation in the KK1 cell line resulted in reduction of the PLC activity, lower rates of proliferation and aggregation, and a marked reduction in chemotaxis towards CCL22. The PLCγ1-pathway inhibitors ibrutinib and ritonavir reduced both the PLC activity and the tested functions of KK1 cells.InterpretationConsistent with observations from clinical studies, our data provide direct evidence that activated variants of the PLCγ1 enzyme contribute to the properties of the malignant T-cell clone in ATL.
AU  - Prawiro,C
AU  - Bunney,TD
AU  - Kampyli,C
AU  - Yaguchi,H
AU  - Katan,M
AU  - Bangham,CRM
DO  - 10.1016/j.bbadis.2022.166601
PY  - 2023///
SN  - 0925-4439
TI  - A frequent PLCγ1 mutation in adult T-cell leukemia/lymphoma determines functional properties of the malignant cells
T2  - BBA: Molecular Basis of Disease
UR  - http://dx.doi.org/10.1016/j.bbadis.2022.166601
UR  - https://www.webofscience.com/api/gateway?GWVersion=2&SrcApp=PARTNER_APP&SrcAuth=LinksAMR&KeyUT=WOS:000931900400004&DestLinkType=FullRecord&DestApp=ALL_WOS&UsrCustomerID=a2bf6146997ec60c407a63945d4e92bb
UR  - https://www.sciencedirect.com/science/article/pii/S0925443922002721
UR  - http://hdl.handle.net/10044/1/109367
VL  - 1869
ER  -
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