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Growth arrest‐specific protein 2 (GAS2) interacts with CXCR4 to promote T‐cell leukemogenesis partially via c‐MYC

Although growth arrest‐specific protein 2 (GAS2) promotes the growth of T‐cell acute lymphoblastic leukemia (T‐ALL) cells in culture, the effect of GAS2 on T‐cell leukemogenesis has not been studied, and the mechanism remains unclear. In the present study, xenograft studies showed that GAS2 silencin...

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Autores principales: Ma, Wenjuan, Wan, Yan, Zhang, Jianxiang, Yao, Jianan, Wang, Yifei, Lu, Jinchang, Liu, Hong, Huang, Xiaorui, Zhang, Xiuyan, Zhou, Haixia, He, Yulong, Wu, Depei, Wang, Jianrong, Zhao, Yun
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9580887/
https://www.ncbi.nlm.nih.gov/pubmed/36054080
http://dx.doi.org/10.1002/1878-0261.13306
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author Ma, Wenjuan
Wan, Yan
Zhang, Jianxiang
Yao, Jianan
Wang, Yifei
Lu, Jinchang
Liu, Hong
Huang, Xiaorui
Zhang, Xiuyan
Zhou, Haixia
He, Yulong
Wu, Depei
Wang, Jianrong
Zhao, Yun
author_facet Ma, Wenjuan
Wan, Yan
Zhang, Jianxiang
Yao, Jianan
Wang, Yifei
Lu, Jinchang
Liu, Hong
Huang, Xiaorui
Zhang, Xiuyan
Zhou, Haixia
He, Yulong
Wu, Depei
Wang, Jianrong
Zhao, Yun
author_sort Ma, Wenjuan
collection PubMed
description Although growth arrest‐specific protein 2 (GAS2) promotes the growth of T‐cell acute lymphoblastic leukemia (T‐ALL) cells in culture, the effect of GAS2 on T‐cell leukemogenesis has not been studied, and the mechanism remains unclear. In the present study, xenograft studies showed that GAS2 silencing impaired T‐cell leukemogenesis and decreased leukemic cell infiltration. Mechanistically, GAS2 regulated the protein expression of C‐X‐C chemokine receptor type 4 (CXCR4) rather than its transcript expression. Immunoprecipitation revealed that GAS2 interacted with CXCR4, and confocal analysis showed that GAS2 was partially co‐expressed with CXCR4, which provided a strong molecular basis for GAS2 to regulate CXCR4 expression. Importantly, CXCR4 overexpression alleviated the inhibitory effect of GAS2 silencing on the growth and migration of T‐ALL cells. Moreover, GAS2 or CXCR4 silencing inhibited the expression of NOTCH1 and c‐MYC. Forced expression of c‐MYC rescued the growth suppression induced by GAS2 or CXCR4 silencing. Meanwhile, GAS2 deficiency, specifically in blood cells, had a mild effect on normal hematopoiesis, including T‐cell development, and GAS2 silencing did not affect the growth of normal human CD3(+) or CD34(+) cells. Overall, our data indicate that GAS2 promotes T‐cell leukemogenesis through its interaction with CXCR4 to activate NOTCH1/c‐MYC, whereas impaired GAS2 expression has a mild effect on normal hematopoiesis. Therefore, our study suggests that targeting the GAS2/CXCR4 axis is a potential therapeutic strategy for T‐ALL.
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spelling pubmed-95808872022-10-20 Growth arrest‐specific protein 2 (GAS2) interacts with CXCR4 to promote T‐cell leukemogenesis partially via c‐MYC Ma, Wenjuan Wan, Yan Zhang, Jianxiang Yao, Jianan Wang, Yifei Lu, Jinchang Liu, Hong Huang, Xiaorui Zhang, Xiuyan Zhou, Haixia He, Yulong Wu, Depei Wang, Jianrong Zhao, Yun Mol Oncol Research Articles Although growth arrest‐specific protein 2 (GAS2) promotes the growth of T‐cell acute lymphoblastic leukemia (T‐ALL) cells in culture, the effect of GAS2 on T‐cell leukemogenesis has not been studied, and the mechanism remains unclear. In the present study, xenograft studies showed that GAS2 silencing impaired T‐cell leukemogenesis and decreased leukemic cell infiltration. Mechanistically, GAS2 regulated the protein expression of C‐X‐C chemokine receptor type 4 (CXCR4) rather than its transcript expression. Immunoprecipitation revealed that GAS2 interacted with CXCR4, and confocal analysis showed that GAS2 was partially co‐expressed with CXCR4, which provided a strong molecular basis for GAS2 to regulate CXCR4 expression. Importantly, CXCR4 overexpression alleviated the inhibitory effect of GAS2 silencing on the growth and migration of T‐ALL cells. Moreover, GAS2 or CXCR4 silencing inhibited the expression of NOTCH1 and c‐MYC. Forced expression of c‐MYC rescued the growth suppression induced by GAS2 or CXCR4 silencing. Meanwhile, GAS2 deficiency, specifically in blood cells, had a mild effect on normal hematopoiesis, including T‐cell development, and GAS2 silencing did not affect the growth of normal human CD3(+) or CD34(+) cells. Overall, our data indicate that GAS2 promotes T‐cell leukemogenesis through its interaction with CXCR4 to activate NOTCH1/c‐MYC, whereas impaired GAS2 expression has a mild effect on normal hematopoiesis. Therefore, our study suggests that targeting the GAS2/CXCR4 axis is a potential therapeutic strategy for T‐ALL. John Wiley and Sons Inc. 2022-09-11 2022-10 /pmc/articles/PMC9580887/ /pubmed/36054080 http://dx.doi.org/10.1002/1878-0261.13306 Text en © 2022 The Authors. Molecular Oncology published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies. https://creativecommons.org/licenses/by/4.0/This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
spellingShingle Research Articles
Ma, Wenjuan
Wan, Yan
Zhang, Jianxiang
Yao, Jianan
Wang, Yifei
Lu, Jinchang
Liu, Hong
Huang, Xiaorui
Zhang, Xiuyan
Zhou, Haixia
He, Yulong
Wu, Depei
Wang, Jianrong
Zhao, Yun
Growth arrest‐specific protein 2 (GAS2) interacts with CXCR4 to promote T‐cell leukemogenesis partially via c‐MYC
title Growth arrest‐specific protein 2 (GAS2) interacts with CXCR4 to promote T‐cell leukemogenesis partially via c‐MYC
title_full Growth arrest‐specific protein 2 (GAS2) interacts with CXCR4 to promote T‐cell leukemogenesis partially via c‐MYC
title_fullStr Growth arrest‐specific protein 2 (GAS2) interacts with CXCR4 to promote T‐cell leukemogenesis partially via c‐MYC
title_full_unstemmed Growth arrest‐specific protein 2 (GAS2) interacts with CXCR4 to promote T‐cell leukemogenesis partially via c‐MYC
title_short Growth arrest‐specific protein 2 (GAS2) interacts with CXCR4 to promote T‐cell leukemogenesis partially via c‐MYC
title_sort growth arrest‐specific protein 2 (gas2) interacts with cxcr4 to promote t‐cell leukemogenesis partially via c‐myc
topic Research Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9580887/
https://www.ncbi.nlm.nih.gov/pubmed/36054080
http://dx.doi.org/10.1002/1878-0261.13306
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