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Cancer Cell International
Published in: Cancer Cell International 1/2019

Open Access 01-12-2019 | Lymphoma | Primary research

ITK inhibition induced in vitro and in vivo anti-tumor activity through downregulating TCR signaling pathway in malignant T cell lymphoma

Authors: Yalu Liu, Xiaogan Wang, Lijuan Deng, Lingyan Ping, Yunfei Shi, Wen Zheng, Ningjing Lin, Xiaopei Wang, Meifeng Tu, Yan Xie, Weiping Liu, Zhitao Ying, Chen Zhang, Zhengying Pan, Xi Wang, Ning Ding, Yuqin Song, Jun Zhu

Published in: Cancer Cell International | Issue 1/2019

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Abstract

Background

Angioimmunoblastic T cell lymphoma (AITL) is a distinct subtype of peripheral T cell lymphoma and associated with poor outcomes. The activation status of T cell receptor (TCR) signaling has recently become a focus of attention in terms of the therapeutic targets. However, the molecular pathogenesis mechanisms and novel therapeutic targets are largely unknown.

Methods

Antibodies specific to phosphorylated ZAP70, ITK and PLCγ1 were used to identify the activation status of intracellular proteins involved in TCR signaling in AITL patients. Malignant T cell lymphoma cells were transduced with a lentiviral construct containing ITK shRNA for cellular and functional assays. The antitumor effects of the selective ITK inhibitor BMS-509744 were determined in vitro and in vivo.

Results

Immunohistochemistry staining showed that more than half of the AITL patients (n = 38) exhibited continuously activated intracellular TCR signaling pathway. Patients positive for phosphorylated ITK showed a lower rate of complete response (20% vs. 75%, P = 0.004) and a shorter progression-free survival (5.17 months vs. 25.1 months, P = 0.022) than patients negative for phosphorylated ITK. Genetic and pharmacological cellular ITK inhibition significantly compromised the proliferation, invasion and migration of malignant T cells. The selective ITK inhibitor BMS-509744 also induced the pro-apoptotic effects and G2/M phase cell cycle arrest in vitro and in vivo. Finally, inhibition of ITK synergistically enhanced the antitumor effect of vincristine and doxorubicin on malignant T cell lymphoma cell lines.

Conclusions

Our findings suggest that ITK may be a novel candidate therapeutic target for the treatment of patients with ITK-expressing malignant T-cell lymphomas.
Appendix
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Metadata
Title
ITK inhibition induced in vitro and in vivo anti-tumor activity through downregulating TCR signaling pathway in malignant T cell lymphoma
Authors
Yalu Liu
Xiaogan Wang
Lijuan Deng
Lingyan Ping
Yunfei Shi
Wen Zheng
Ningjing Lin
Xiaopei Wang
Meifeng Tu
Yan Xie
Weiping Liu
Zhitao Ying
Chen Zhang
Zhengying Pan
Xi Wang
Ning Ding
Yuqin Song
Jun Zhu
Publication date
01-12-2019
Publisher
BioMed Central
Keyword
Lymphoma
Published in
Cancer Cell International / Issue 1/2019
Electronic ISSN: 1475-2867
DOI
https://doi.org/10.1186/s12935-019-0754-9

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