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Characteristics of TCR?, ZAP-70, and Fc?RI? gene expression in patients with T- and NK/T-cell lymphoma.

ABSTRACT: Abnormal expression of key signaling molecules and defective T-cell function play a crucial role in the pathogenesis of T-cell immunodeficiency in hematological malignancies. To understand the molecular basis of T-cell signaling abnormalities and TCR? chain deficiencies in T- and NK/T-cell lymphoma, the expression level of the TCR?, ZAP-70, and Fc?RI? genes in peripheral blood mononuclear cells from 25 patients with T-cell lymphoma, 16 patients with NK/T-cell lymphoma (NK/T-CL), and 26 healthy individuals was determined. In addition, their relationship with disease stage and TCR? 3' untranslated region (3'UTR) splice variants was analyzed in this study. The expression level of all three genes was significantly altered with disease progression, and a decreasing trend was found in patients compared with healthy controls. TCR? and ZAP-70 were significantly positively related in all samples, and a negative relationship between TCR? and Fc?RI? was significantly lost in NK/T-CL patients. Moreover, distinct expression patterns were defined for patient groups with different TCR? 3'UTR isoforms. In conclusion, a lower expression pattern for all three genes may indicate a weaker immune status based on reduced TCR? and ZAP-70 expression without the complementary effects of Fc?RI?, while aberrant TCR? 3'UTR splicing may contribute to T-cell receptor (TCR) signaling regulation in T cells from patients with T- and NK/T-cell lymphoma.

SUBMITTER: Liao Z

PROVIDER: S-EPMC4337460 | biostudies-literature | 2015 Mar

REPOSITORIES: biostudies-literature

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Characteristics of TCRζ, ZAP-70, and FcɛRIγ gene expression in patients with T- and NK/T-cell lymphoma.

Liao Ziwei Z Zhou Lingling L Wang Chunyan C He Zhifeng Z Wang Xu X Luo Xiaodan X Chen Shaohua S Yang Lijian L Tan Huo H Li Yangqiu Y

DNA and cell biology 20141216 3

Abnormal expression of key signaling molecules and defective T-cell function play a crucial role in the pathogenesis of T-cell immunodeficiency in hematological malignancies. To understand the molecular basis of T-cell signaling abnormalities and TCRζ chain deficiencies in T- and NK/T-cell lymphoma, the expression level of the TCRζ, ZAP-70, and FcɛRIγ genes in peripheral blood mononuclear cells from 25 patients with T-cell lymphoma, 16 patients with NK/T-cell lymphoma (NK/T-CL), and 26 healthy i ...[more]

PMID: 25513989

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Project description: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.

Dataset Information

Characteristics of TCR?, ZAP-70, and Fc?RI? gene expression in patients with T- and NK/T-cell lymphoma.

Publications

Characteristics of TCRζ, ZAP-70, and FcɛRIγ gene expression in patients with T- and NK/T-cell lymphoma.

Similar Datasets

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