Therapeutic inhibition of GAS6-AS1/YBX1/MYC axis suppresses cell propagation and disease progression of acute myeloid leukemia

Abstract Background Acute myeloid leukemia (AML) is the most common type of leukemia in adults. Its therapy has not significantly improved during the past four decades despite intense research efforts. New molecularly targeted therapies are in great need. The proto-oncogene c-Myc (MYC) is an attract...

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Autores principales:	Hao Zhou, Wei Liu, Yongming Zhou, Zhenya Hong, Jian Ni, Xiaoping Zhang, Ziping Li, Mengyuan Li, Wenjuan He, Donghua Zhang, Xuexing Chen, Jianhua Zhu
Formato:	article
Lenguaje:	EN
Publicado:	BMC 2021
Materias:	Oncogene GAS6-AS1 MYC YBX1 RNA-binding protein Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
Acceso en línea:	https://doaj.org/article/ea05389eaa4442eea576c26ad9e9992d
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spelling	oai:doaj.org-article:ea05389eaa4442eea576c26ad9e9992d2021-11-14T12:15:25ZTherapeutic inhibition of GAS6-AS1/YBX1/MYC axis suppresses cell propagation and disease progression of acute myeloid leukemia10.1186/s13046-021-02145-91756-9966https://doaj.org/article/ea05389eaa4442eea576c26ad9e9992d2021-11-01T00:00:00Zhttps://doi.org/10.1186/s13046-021-02145-9https://doaj.org/toc/1756-9966Abstract Background Acute myeloid leukemia (AML) is the most common type of leukemia in adults. Its therapy has not significantly improved during the past four decades despite intense research efforts. New molecularly targeted therapies are in great need. The proto-oncogene c-Myc (MYC) is an attractive target due to its transactivation role in multiple signaling cascades. Deregulation of the MYC is considered one of a series of oncogenic events required for tumorigenesis. However, limited knowledge is available on which mechanism underlie MYC dysregulation and how long non-coding RNAs (lncRNAs) are involved in MYC dysregulation in AML. Methods AML microarray chips and public datasets were screened to identify novel lncRNA GAS6-AS1 was dysregulated in AML. Gain or loss of functional leukemia cell models were produced, and in vitro and in vivo experiments were applied to demonstrate its leukemogenic phenotypes. Interactive network analyses were performed to define intrinsic mechanism. Results We identified GAS6-AS1 was overexpressed in AML, and its aberrant function lead to more aggressive leukemia phenotypes and poorer survival outcomes. We revealed that GAS6-AS1 directly binds Y-box binding protein 1 (YBX1) to facilitate its interaction with MYC, leading to MYC transactivation and upregulation of IL1R1, RAB27B and other MYC target genes associated with leukemia progression. Further, lentiviral-based GAS6-AS1 silencing inhibited leukemia progression in vivo. Conclusions Our findings revealed a previously unappreciated role of GAS6-AS1 as an oncogenic lncRNA in AML progression and prognostic prediction. Importantly, we demonstrated that therapeutic targeting of the GAS6-AS1/YBX1/MYC axis inhibits AML cellular propagation and disease progression. Our insight in lncRNA associated MYC-driven leukemogenesis may contribute to develop new anti-leukemia treatment strategies.Hao ZhouWei LiuYongming ZhouZhenya HongJian NiXiaoping ZhangZiping LiMengyuan LiWenjuan HeDonghua ZhangXuexing ChenJianhua ZhuBMCarticleOncogeneGAS6-AS1MYCYBX1RNA-binding proteinNeoplasms. Tumors. Oncology. Including cancer and carcinogensRC254-282ENJournal of Experimental & Clinical Cancer Research, Vol 40, Iss 1, Pp 1-17 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Oncogene GAS6-AS1 MYC YBX1 RNA-binding protein Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
spellingShingle	Oncogene GAS6-AS1 MYC YBX1 RNA-binding protein Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282 Hao Zhou Wei Liu Yongming Zhou Zhenya Hong Jian Ni Xiaoping Zhang Ziping Li Mengyuan Li Wenjuan He Donghua Zhang Xuexing Chen Jianhua Zhu Therapeutic inhibition of GAS6-AS1/YBX1/MYC axis suppresses cell propagation and disease progression of acute myeloid leukemia
description	Abstract Background Acute myeloid leukemia (AML) is the most common type of leukemia in adults. Its therapy has not significantly improved during the past four decades despite intense research efforts. New molecularly targeted therapies are in great need. The proto-oncogene c-Myc (MYC) is an attractive target due to its transactivation role in multiple signaling cascades. Deregulation of the MYC is considered one of a series of oncogenic events required for tumorigenesis. However, limited knowledge is available on which mechanism underlie MYC dysregulation and how long non-coding RNAs (lncRNAs) are involved in MYC dysregulation in AML. Methods AML microarray chips and public datasets were screened to identify novel lncRNA GAS6-AS1 was dysregulated in AML. Gain or loss of functional leukemia cell models were produced, and in vitro and in vivo experiments were applied to demonstrate its leukemogenic phenotypes. Interactive network analyses were performed to define intrinsic mechanism. Results We identified GAS6-AS1 was overexpressed in AML, and its aberrant function lead to more aggressive leukemia phenotypes and poorer survival outcomes. We revealed that GAS6-AS1 directly binds Y-box binding protein 1 (YBX1) to facilitate its interaction with MYC, leading to MYC transactivation and upregulation of IL1R1, RAB27B and other MYC target genes associated with leukemia progression. Further, lentiviral-based GAS6-AS1 silencing inhibited leukemia progression in vivo. Conclusions Our findings revealed a previously unappreciated role of GAS6-AS1 as an oncogenic lncRNA in AML progression and prognostic prediction. Importantly, we demonstrated that therapeutic targeting of the GAS6-AS1/YBX1/MYC axis inhibits AML cellular propagation and disease progression. Our insight in lncRNA associated MYC-driven leukemogenesis may contribute to develop new anti-leukemia treatment strategies.
format	article
author	Hao Zhou Wei Liu Yongming Zhou Zhenya Hong Jian Ni Xiaoping Zhang Ziping Li Mengyuan Li Wenjuan He Donghua Zhang Xuexing Chen Jianhua Zhu
author_facet	Hao Zhou Wei Liu Yongming Zhou Zhenya Hong Jian Ni Xiaoping Zhang Ziping Li Mengyuan Li Wenjuan He Donghua Zhang Xuexing Chen Jianhua Zhu
author_sort	Hao Zhou
title	Therapeutic inhibition of GAS6-AS1/YBX1/MYC axis suppresses cell propagation and disease progression of acute myeloid leukemia
title_short	Therapeutic inhibition of GAS6-AS1/YBX1/MYC axis suppresses cell propagation and disease progression of acute myeloid leukemia
title_full	Therapeutic inhibition of GAS6-AS1/YBX1/MYC axis suppresses cell propagation and disease progression of acute myeloid leukemia
title_fullStr	Therapeutic inhibition of GAS6-AS1/YBX1/MYC axis suppresses cell propagation and disease progression of acute myeloid leukemia
title_full_unstemmed	Therapeutic inhibition of GAS6-AS1/YBX1/MYC axis suppresses cell propagation and disease progression of acute myeloid leukemia
title_sort	therapeutic inhibition of gas6-as1/ybx1/myc axis suppresses cell propagation and disease progression of acute myeloid leukemia
publisher	BMC
publishDate	2021
url	https://doaj.org/article/ea05389eaa4442eea576c26ad9e9992d
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Therapeutic inhibition of GAS6-AS1/YBX1/MYC axis suppresses cell propagation and disease progression of acute myeloid leukemia

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