Please use this identifier to cite or link to this item: https://doi.org/10.1371/journal.pone.0261469
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dc.titleT and NK cell lymphoma cell lines do not rely on ZAP-70 for survival
dc.contributor.authorde Mel, Sanjay
dc.contributor.authorMustafa, Nurulhuda
dc.contributor.authorSelvarajan, Viknesvaran
dc.contributor.authorAzaman, Muhammad Irfan
dc.contributor.authorJaynes, Patrick William
dc.contributor.authorVenguidessane, Shruthi
dc.contributor.authorPhuong, Hoang Mai
dc.contributor.authorAlnaseri, Zubaida Talal
dc.contributor.authorPhyu, The
dc.contributor.authorGirard, Louis-Pierre
dc.contributor.authorChng, Wee Joo
dc.contributor.authorWardyn, Joanna
dc.contributor.authorLi, Ying
dc.contributor.authorAn, Omer
dc.contributor.authorYang, Henry
dc.contributor.authorNg, Siok Bian
dc.contributor.authorJeyasekharan, Anand D
dc.date.accessioned2022-07-12T02:15:33Z
dc.date.available2022-07-12T02:15:33Z
dc.date.issued2022-01-25
dc.identifier.citationde Mel, Sanjay, Mustafa, Nurulhuda, Selvarajan, Viknesvaran, Azaman, Muhammad Irfan, Jaynes, Patrick William, Venguidessane, Shruthi, Phuong, Hoang Mai, Alnaseri, Zubaida Talal, Phyu, The, Girard, Louis-Pierre, Chng, Wee Joo, Wardyn, Joanna, Li, Ying, An, Omer, Yang, Henry, Ng, Siok Bian, Jeyasekharan, Anand D (2022-01-25). T and NK cell lymphoma cell lines do not rely on ZAP-70 for survival. PLOS ONE 17 (1). ScholarBank@NUS Repository. https://doi.org/10.1371/journal.pone.0261469
dc.identifier.issn19326203
dc.identifier.urihttps://scholarbank.nus.edu.sg/handle/10635/228205
dc.description.abstractB-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.
dc.language.isoen
dc.publisherPUBLIC LIBRARY SCIENCE
dc.sourceElements
dc.subjectScience & Technology
dc.subjectMultidisciplinary Sciences
dc.subjectScience & Technology - Other Topics
dc.subjectPROTEIN-TYROSINE KINASE
dc.subjectSEVERE COMBINED IMMUNODEFICIENCY
dc.subjectFUSION KINASE
dc.subjectRECEPTOR
dc.subjectSYK
dc.subjectITK
dc.subjectACTIVATION
dc.subjectEXPRESSION
dc.subjectAPOPTOSIS
dc.subjectDISEASE
dc.typeArticle
dc.date.updated2022-07-06T05:50:16Z
dc.contributor.departmentCANCER SCIENCE INSTITUTE OF SINGAPORE
dc.contributor.departmentMEDICINE
dc.contributor.departmentPATHOLOGY
dc.description.doi10.1371/journal.pone.0261469
dc.description.sourcetitlePLOS ONE
dc.description.volume17
dc.description.issue1
dc.published.statePublished
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