ALOX5 exhibits anti-tumor and drug-sensitizing effects in MLL-rearranged leukemia

Abstract MLL-rearranged acute myeloid leukemia (AML) remains a fatal disease with a high rate of relapse and therapeutic failure due to chemotherapy resistance. In analysis of our Affymetrix microarray profiling and chromatin immunoprecipitation (ChIP) assays, we found that ALOX5 is especially down-...

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Autores principales:	Yungui Wang, Jennifer R. Skibbe, Chao Hu, Lei Dong, Kyle Ferchen, Rui Su, Chenying Li, Hao Huang, Hengyou Weng, Huilin Huang, Xi Qin, Jie Jin, Jianjun Chen, Xi Jiang
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2017
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/f693c34a5ab845d5aef3a46dd809a2a8
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spelling	oai:doaj.org-article:f693c34a5ab845d5aef3a46dd809a2a82021-12-02T12:30:37ZALOX5 exhibits anti-tumor and drug-sensitizing effects in MLL-rearranged leukemia10.1038/s41598-017-01913-y2045-2322https://doaj.org/article/f693c34a5ab845d5aef3a46dd809a2a82017-05-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-01913-yhttps://doaj.org/toc/2045-2322Abstract MLL-rearranged acute myeloid leukemia (AML) remains a fatal disease with a high rate of relapse and therapeutic failure due to chemotherapy resistance. In analysis of our Affymetrix microarray profiling and chromatin immunoprecipitation (ChIP) assays, we found that ALOX5 is especially down-regulated in MLL-rearranged AML, via transcription repression mediated by Polycomb repressive complex 2 (PRC2). Colony forming/replating and bone marrow transplantation (BMT) assays showed that Alox5 exhibited a moderate anti-tumor effect both in vitro and in vivo. Strikingly, leukemic cells with Alox5 overexpression showed a significantly higher sensitivity to the standard chemotherapeutic agents, i.e., doxorubicin (DOX) and cytarabine (Ara-C). The drug-sensitizing role of Alox5 was further confirmed in human and murine MLL-rearranged AML cell models in vitro, as well as in the in vivo MLL-rearranged AML BMT model coupled with treatment of “5 + 3” (i.e. DOX plus Ara-C) regimen. Stat and K-Ras signaling pathways were negatively correlated with Alox5 overexpression in MLL-AF9-leukemic blast cells; inhibition of the above signaling pathways mimicked the drug-sensitizing effect of ALOX5 in AML cells. Collectively, our work shows that ALOX5 plays a moderate anti-tumor role and functions as a drug sensitizer, with a therapeutic potential, in MLL-rearranged AML.Yungui WangJennifer R. SkibbeChao HuLei DongKyle FerchenRui SuChenying LiHao HuangHengyou WengHuilin HuangXi QinJie JinJianjun ChenXi JiangNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-11 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Yungui Wang Jennifer R. Skibbe Chao Hu Lei Dong Kyle Ferchen Rui Su Chenying Li Hao Huang Hengyou Weng Huilin Huang Xi Qin Jie Jin Jianjun Chen Xi Jiang ALOX5 exhibits anti-tumor and drug-sensitizing effects in MLL-rearranged leukemia
description	Abstract MLL-rearranged acute myeloid leukemia (AML) remains a fatal disease with a high rate of relapse and therapeutic failure due to chemotherapy resistance. In analysis of our Affymetrix microarray profiling and chromatin immunoprecipitation (ChIP) assays, we found that ALOX5 is especially down-regulated in MLL-rearranged AML, via transcription repression mediated by Polycomb repressive complex 2 (PRC2). Colony forming/replating and bone marrow transplantation (BMT) assays showed that Alox5 exhibited a moderate anti-tumor effect both in vitro and in vivo. Strikingly, leukemic cells with Alox5 overexpression showed a significantly higher sensitivity to the standard chemotherapeutic agents, i.e., doxorubicin (DOX) and cytarabine (Ara-C). The drug-sensitizing role of Alox5 was further confirmed in human and murine MLL-rearranged AML cell models in vitro, as well as in the in vivo MLL-rearranged AML BMT model coupled with treatment of “5 + 3” (i.e. DOX plus Ara-C) regimen. Stat and K-Ras signaling pathways were negatively correlated with Alox5 overexpression in MLL-AF9-leukemic blast cells; inhibition of the above signaling pathways mimicked the drug-sensitizing effect of ALOX5 in AML cells. Collectively, our work shows that ALOX5 plays a moderate anti-tumor role and functions as a drug sensitizer, with a therapeutic potential, in MLL-rearranged AML.
format	article
author	Yungui Wang Jennifer R. Skibbe Chao Hu Lei Dong Kyle Ferchen Rui Su Chenying Li Hao Huang Hengyou Weng Huilin Huang Xi Qin Jie Jin Jianjun Chen Xi Jiang
author_facet	Yungui Wang Jennifer R. Skibbe Chao Hu Lei Dong Kyle Ferchen Rui Su Chenying Li Hao Huang Hengyou Weng Huilin Huang Xi Qin Jie Jin Jianjun Chen Xi Jiang
author_sort	Yungui Wang
title	ALOX5 exhibits anti-tumor and drug-sensitizing effects in MLL-rearranged leukemia
title_short	ALOX5 exhibits anti-tumor and drug-sensitizing effects in MLL-rearranged leukemia
title_full	ALOX5 exhibits anti-tumor and drug-sensitizing effects in MLL-rearranged leukemia
title_fullStr	ALOX5 exhibits anti-tumor and drug-sensitizing effects in MLL-rearranged leukemia
title_full_unstemmed	ALOX5 exhibits anti-tumor and drug-sensitizing effects in MLL-rearranged leukemia
title_sort	alox5 exhibits anti-tumor and drug-sensitizing effects in mll-rearranged leukemia
publisher	Nature Portfolio
publishDate	2017
url	https://doaj.org/article/f693c34a5ab845d5aef3a46dd809a2a8
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ALOX5 exhibits anti-tumor and drug-sensitizing effects in MLL-rearranged leukemia

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