Spleen Tyrosine Kinase Inhibitor TAK-659 Prevents Splenomegaly and Tumor Development in a Murine Model of Epstein-Barr Virus-Associated Lymphoma

ABSTRACT Epstein-Barr virus (EBV) is associated with several B and epithelial cell cancers. EBV-encoded latent membrane protein 2A (LMP2A) contributes to cellular transformation by mimicking B cell receptor signaling. LMP2A/MYC double transgenic mice develop splenomegaly and B cell lymphoma much fas...

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Autores principales:	Osman Cen, Karuppiah Kannan, Jessica Huck Sappal, Jie Yu, Mengkun Zhang, Muzaffer Arikan, Ali Ucur, Duran Ustek, Yeter Cen, Leo Gordon, Richard Longnecker
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2018
Materias:	Burkitt’s lymphoma EBV-related cancer LMP2A SYK TAK-659 Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/48f85aa45d2b44e28e440291bf2c7228
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spelling	oai:doaj.org-article:48f85aa45d2b44e28e440291bf2c72282021-11-15T15:25:50ZSpleen Tyrosine Kinase Inhibitor TAK-659 Prevents Splenomegaly and Tumor Development in a Murine Model of Epstein-Barr Virus-Associated Lymphoma10.1128/mSphereDirect.00378-182379-5042https://doaj.org/article/48f85aa45d2b44e28e440291bf2c72282018-08-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mSphereDirect.00378-18https://doaj.org/toc/2379-5042ABSTRACT Epstein-Barr virus (EBV) is associated with several B and epithelial cell cancers. EBV-encoded latent membrane protein 2A (LMP2A) contributes to cellular transformation by mimicking B cell receptor signaling. LMP2A/MYC double transgenic mice develop splenomegaly and B cell lymphoma much faster than MYC transgenic mice do. In this study, we explored the potential therapeutic efficacy of a novel spleen tyrosine kinase (SYK) and FLT3 inhibitor TAK-659 for development of a treatment option for EBV-associated malignancies. In our transgenic model, TAK-659 treatment totally abrogated splenomegaly and tumor development in LMP2A/MYC mice in both pretumor and tumor cell transfer experiments. TAK-659 treatment killed tumor cells, but not host cells within the spleen and tumors. Furthermore, TAK-659 treatment abrogated metastasis of tumor cells into bone marrow. Our data also show that TAK-659 inhibits SYK phosphorylation and induces apoptosis in LMP2A/MYC tumor cells at low nanomolar concentrations. Therefore, TAK-659 may provide an effective therapeutic option for treatment of LMP2A-positive EBV-associated malignancies and should be explored further in clinical trials. IMPORTANCE The novel SYK and FLT3 inhibitor TAK-659 prevents the enlargement of spleen and tumor development in a mouse model of EBV-associated lymphoma by counteracting the activation of cellular kinase SYK through the viral LMP2A gene by inducing cell death in tumor cells but not in nontumor cells. These findings indicate that TAK-659 may be a very effective nontoxic therapeutic molecule especially for EBV-positive hematologic malignancies.Osman CenKaruppiah KannanJessica Huck SappalJie YuMengkun ZhangMuzaffer ArikanAli UcurDuran UstekYeter CenLeo GordonRichard LongneckerAmerican Society for MicrobiologyarticleBurkitt’s lymphomaEBV-related cancerLMP2ASYKTAK-659MicrobiologyQR1-502ENmSphere, Vol 3, Iss 4 (2018)
institution	DOAJ
collection	DOAJ
language	EN
topic	Burkitt’s lymphoma EBV-related cancer LMP2A SYK TAK-659 Microbiology QR1-502
spellingShingle	Burkitt’s lymphoma EBV-related cancer LMP2A SYK TAK-659 Microbiology QR1-502 Osman Cen Karuppiah Kannan Jessica Huck Sappal Jie Yu Mengkun Zhang Muzaffer Arikan Ali Ucur Duran Ustek Yeter Cen Leo Gordon Richard Longnecker Spleen Tyrosine Kinase Inhibitor TAK-659 Prevents Splenomegaly and Tumor Development in a Murine Model of Epstein-Barr Virus-Associated Lymphoma
description	ABSTRACT Epstein-Barr virus (EBV) is associated with several B and epithelial cell cancers. EBV-encoded latent membrane protein 2A (LMP2A) contributes to cellular transformation by mimicking B cell receptor signaling. LMP2A/MYC double transgenic mice develop splenomegaly and B cell lymphoma much faster than MYC transgenic mice do. In this study, we explored the potential therapeutic efficacy of a novel spleen tyrosine kinase (SYK) and FLT3 inhibitor TAK-659 for development of a treatment option for EBV-associated malignancies. In our transgenic model, TAK-659 treatment totally abrogated splenomegaly and tumor development in LMP2A/MYC mice in both pretumor and tumor cell transfer experiments. TAK-659 treatment killed tumor cells, but not host cells within the spleen and tumors. Furthermore, TAK-659 treatment abrogated metastasis of tumor cells into bone marrow. Our data also show that TAK-659 inhibits SYK phosphorylation and induces apoptosis in LMP2A/MYC tumor cells at low nanomolar concentrations. Therefore, TAK-659 may provide an effective therapeutic option for treatment of LMP2A-positive EBV-associated malignancies and should be explored further in clinical trials. IMPORTANCE The novel SYK and FLT3 inhibitor TAK-659 prevents the enlargement of spleen and tumor development in a mouse model of EBV-associated lymphoma by counteracting the activation of cellular kinase SYK through the viral LMP2A gene by inducing cell death in tumor cells but not in nontumor cells. These findings indicate that TAK-659 may be a very effective nontoxic therapeutic molecule especially for EBV-positive hematologic malignancies.
format	article
author	Osman Cen Karuppiah Kannan Jessica Huck Sappal Jie Yu Mengkun Zhang Muzaffer Arikan Ali Ucur Duran Ustek Yeter Cen Leo Gordon Richard Longnecker
author_facet	Osman Cen Karuppiah Kannan Jessica Huck Sappal Jie Yu Mengkun Zhang Muzaffer Arikan Ali Ucur Duran Ustek Yeter Cen Leo Gordon Richard Longnecker
author_sort	Osman Cen
title	Spleen Tyrosine Kinase Inhibitor TAK-659 Prevents Splenomegaly and Tumor Development in a Murine Model of Epstein-Barr Virus-Associated Lymphoma
title_short	Spleen Tyrosine Kinase Inhibitor TAK-659 Prevents Splenomegaly and Tumor Development in a Murine Model of Epstein-Barr Virus-Associated Lymphoma
title_full	Spleen Tyrosine Kinase Inhibitor TAK-659 Prevents Splenomegaly and Tumor Development in a Murine Model of Epstein-Barr Virus-Associated Lymphoma
title_fullStr	Spleen Tyrosine Kinase Inhibitor TAK-659 Prevents Splenomegaly and Tumor Development in a Murine Model of Epstein-Barr Virus-Associated Lymphoma
title_full_unstemmed	Spleen Tyrosine Kinase Inhibitor TAK-659 Prevents Splenomegaly and Tumor Development in a Murine Model of Epstein-Barr Virus-Associated Lymphoma
title_sort	spleen tyrosine kinase inhibitor tak-659 prevents splenomegaly and tumor development in a murine model of epstein-barr virus-associated lymphoma
publisher	American Society for Microbiology
publishDate	2018
url	https://doaj.org/article/48f85aa45d2b44e28e440291bf2c7228
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Spleen Tyrosine Kinase Inhibitor TAK-659 Prevents Splenomegaly and Tumor Development in a Murine Model of Epstein-Barr Virus-Associated Lymphoma

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