PMID- 35077445
OWN - NLM
STAT- MEDLINE
DCOM- 20220210
LR  - 20220210
IS  - 1932-6203 (Electronic)
IS  - 1932-6203 (Linking)
VI  - 17
IP  - 1
DP  - 2022
TI  - T and NK cell lymphoma cell lines do not rely on ZAP-70 for survival.
PG  - e0261469
LID - 10.1371/journal.pone.0261469 [doi]
LID - e0261469
AB  - B-cell receptor (BCR) signalling is critical for the survival of B-cell lymphomas 
      and is a therapeutic target of drugs such as Ibrutinib. However, the role of 
      T-cell receptor (TCR) signalling in the survival of T/Natural Killer (NK) 
      lymphomas is not clear. ZAP-70 (zeta associated protein-70) is a cytoplasmic 
      tyrosine kinase with a critical role in T-cell receptor (TCR) signalling. It has 
      also been shown to play a role in normal NK cell signalling and activation. High 
      ZAP-70 expression has been detected by immunohistochemistry in peripheral T cell 
      lymphoma (PTCL) and NK cell lymphomas (NKTCL). We therefore, studied the role of 
      TCR pathways in mediating the proliferation and survival of these malignancies 
      through ZAP-70 signalling. ZAP-70 protein was highly expressed in T cell lymphoma 
      cell lines (JURKAT and KARPAS-299) and NKTCL cell lines (KHYG-1, HANK-1, NK-YS, 
      SNK-1 and SNK-6), but not in multiple B-cell lymphoma cell lines. siRNA depletion 
      of ZAP-70 suppressed the phosphorylation of ZAP-70 substrates, SLP76, LAT and 
      p38MAPK, but did not affect cell viability or induce apoptosis in these cell 
      lines. Similarly, while stable overexpression of ZAP-70 mediates increased 
      phosphorylation of target substrates in the TCR pathway, it does not promote 
      increased survival or growth of NKTCL cell lines. The epidermal growth factor 
      receptor (EGFR) inhibitor Gefitinib, which has off-target activity against 
      ZAP-70, also did not show any differential cell kill between ZAP-70 
      overexpressing (OE) or knockdown (KD) cell lines. Whole transcriptome RNA 
      sequencing highlighted that there was very minimal differential gene expression 
      in three different T/NK cell lines induced by ZAP-70 KD. Importantly, ZAP-70 KD 
      did not significantly enrich for any downstream TCR related genes and pathways. 
      Altogether, this suggests that high expression and constitutive signalling of 
      ZAP-70 in T/NK lymphoma is not critical for cell survival or downstream 
      TCR-mediated signalling and gene expression. ZAP-70 therefore may not be a 
      suitable therapeutic target in T/NK cell malignancies.
FAU - de Mel, Sanjay
AU  - de Mel S
AUID- ORCID: 0000-0002-8881-3537
AD  - Department of Haematology Oncology, National University Cancer Institute 
      Singapore, National University Health System Singapore, Singapore, Singapore.
FAU - Mustafa, Nurulhuda
AU  - Mustafa N
AD  - Department of Medicine, Yong Loo Lin School of Medicine, National University of 
      Singapore, Singapore, Singapore.
FAU - Selvarajan, Viknesvaran
AU  - Selvarajan V
AUID- ORCID: 0000-0002-6017-3902
AD  - Department of Pathology Yong Loo Lin School of Medicine, National University of 
      Singapore, Singapore, Singapore.
FAU - Azaman, Muhammad Irfan
AU  - Azaman MI
AD  - Cancer Science Institute of Singapore, National University of Singapore, 
      Singapore, Singapore.
FAU - Jaynes, Patrick William
AU  - Jaynes PW
AD  - Cancer Science Institute of Singapore, National University of Singapore, 
      Singapore, Singapore.
FAU - Venguidessane, Shruthi
AU  - Venguidessane S
AD  - Cancer Science Institute of Singapore, National University of Singapore, 
      Singapore, Singapore.
FAU - Phuong, Hoang Mai
AU  - Phuong HM
AD  - Cancer Science Institute of Singapore, National University of Singapore, 
      Singapore, Singapore.
FAU - Alnaseri, Zubaida Talal
AU  - Alnaseri ZT
AD  - Cancer Science Institute of Singapore, National University of Singapore, 
      Singapore, Singapore.
FAU - Phyu, The
AU  - Phyu T
AD  - Department of Pathology Yong Loo Lin School of Medicine, National University of 
      Singapore, Singapore, Singapore.
AD  - Cancer Science Institute of Singapore, National University of Singapore, 
      Singapore, Singapore.
FAU - Girard, Louis-Pierre
AU  - Girard LP
AD  - School of Medicine, University of Aberdeen, Aberdeen, United Kingdom.
AD  - Aberdeen Royal Infirmary, NHS Grampian, Scotland, United Kingdom.
FAU - Chng, Wee Joo
AU  - Chng WJ
AD  - Department of Haematology Oncology, National University Cancer Institute 
      Singapore, National University Health System Singapore, Singapore, Singapore.
AD  - Department of Medicine, Yong Loo Lin School of Medicine, National University of 
      Singapore, Singapore, Singapore.
AD  - Cancer Science Institute of Singapore, National University of Singapore, 
      Singapore, Singapore.
FAU - Wardyn, Joanna
AU  - Wardyn J
AD  - Cancer Science Institute of Singapore, National University of Singapore, 
      Singapore, Singapore.
FAU - Li, Ying
AU  - Li Y
AD  - Cancer Science Institute of Singapore, National University of Singapore, 
      Singapore, Singapore.
FAU - An, Omer
AU  - An O
AUID- ORCID: 0000-0002-5762-6253
AD  - Cancer Science Institute of Singapore, National University of Singapore, 
      Singapore, Singapore.
FAU - Yang, Henry
AU  - Yang H
AD  - Cancer Science Institute of Singapore, National University of Singapore, 
      Singapore, Singapore.
FAU - Ng, Siok Bian
AU  - Ng SB
AD  - Department of Pathology Yong Loo Lin School of Medicine, National University of 
      Singapore, Singapore, Singapore.
AD  - Cancer Science Institute of Singapore, National University of Singapore, 
      Singapore, Singapore.
FAU - Jeyasekharan, Anand D
AU  - Jeyasekharan AD
AD  - Department of Haematology Oncology, National University Cancer Institute 
      Singapore, National University Health System Singapore, Singapore, Singapore.
AD  - Department of Medicine, Yong Loo Lin School of Medicine, National University of 
      Singapore, Singapore, Singapore.
AD  - Cancer Science Institute of Singapore, National University of Singapore, 
      Singapore, Singapore.
LA  - eng
PT  - Journal Article
DEP - 20220125
PL  - United States
TA  - PLoS One
JT  - PloS one
JID - 101285081
RN  - EC 2.7.10.2 (ZAP-70 Protein-Tyrosine Kinase)
RN  - EC 2.7.10.2 (ZAP70 protein, human)
RN  - S65743JHBS (Gefitinib)
SB  - IM
MH  - Cell Line, Tumor
MH  - Cell Proliferation/drug effects
MH  - Cell Survival/drug effects
MH  - Gefitinib/*pharmacology
MH  - Gene Expression Regulation, Neoplastic
MH  - Gene Knockdown Techniques
MH  - Humans
MH  - Jurkat Cells
MH  - Lymphoma, Extranodal NK-T-Cell/genetics/*metabolism
MH  - Lymphoma, T-Cell, Peripheral/genetics/*metabolism
MH  - Phosphorylation/drug effects
MH  - Signal Transduction/drug effects
MH  - *Up-Regulation
MH  - ZAP-70 Protein-Tyrosine Kinase/genetics/*metabolism
PMC - PMC8789098
COIS- the authors have declared that no competing interests exist.
EDAT- 2022/01/26 06:00
MHDA- 2022/02/11 06:00
PMCR- 2022/01/25
CRDT- 2022/01/25 17:10
PHST- 2021/05/02 00:00 [received]
PHST- 2021/12/02 00:00 [accepted]
PHST- 2022/01/25 17:10 [entrez]
PHST- 2022/01/26 06:00 [pubmed]
PHST- 2022/02/11 06:00 [medline]
PHST- 2022/01/25 00:00 [pmc-release]
AID - PONE-D-21-14507 [pii]
AID - 10.1371/journal.pone.0261469 [doi]
PST - epublish
SO  - PLoS One. 2022 Jan 25;17(1):e0261469. doi: 10.1371/journal.pone.0261469. 
      eCollection 2022.