Oncotarget

Research Papers:

Upregulation of CD11b and CD86 through LSD1 inhibition promotes myeloid differentiation and suppresses cell proliferation in human monocytic leukemia cells

Jianwu Fang, Haiyan Ying, Ting Mao, Yanjia Fang, Yuan Lu, He Wang, Irene Zang, Zhaofu Wang, Ying Lin, Mengxi Zhao, Xiao Luo, Zongyao Wang, Yan Zhang, Chao Zhang, Wei Xiao, Yan Wang, Wei Tan, Zhui Chen, Chris Lu, Peter Atadja, En Li, Kehao Zhao _, Jianfeng Liu and Justin Gu

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Oncotarget. 2017; 8:85085-85101. https://doi.org/10.18632/oncotarget.18564

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Abstract

Jianwu Fang1,2, Haiyan Ying2, Ting Mao2, Yanjia Fang2, Yuan Lu2, He Wang2, Irene Zang2, Zhaofu Wang2, Ying Lin2, Mengxi Zhao2, Xiao Luo2, Zongyao Wang2, Yan Zhang2, Chao Zhang2, Wei Xiao2, Yan Wang2, Wei Tan2, Zhui Chen2, Chris Lu2, Peter Atadja2, En Li2, Kehao Zhao2, Jianfeng Liu1 and Justin Gu2

1Key Laboratory of Molecular Biophysics of Ministry of Education, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan 430074, China

2China Novartis Institutes for BioMedical Research, Pudong New Area, Shanghai 201203, China

Correspondence to:

Kehao Zhao, email: kehaozhao@gmail.com

Jianfeng Liu, email: jfliu@mail.hust.edu.cn

Justin Gu, email: justin.gu@novartis.com

Keywords: LSD1, CD11b, CD86, myeloid differentiation, monocytic leukemia

Received: October 22, 2016     Accepted: June 02, 2017     Published: June 19, 2017

ABSTRACT

LSD1 (Lysine Specific Demethylase1)/KDM1A (Lysine Demethylase 1A), a flavin adenine dinucleotide (FAD)-dependent histone H3K4/K9 demethylase, sustains oncogenic potential of leukemia stem cells in primary human leukemia cells. However, the pro-differentiation and anti-proliferation effects of LSD1 inhibition in acute myeloid leukemia (AML) are not yet fully understood. Here, we report that small hairpin RNA (shRNA) mediated LSD1 inhibition causes a remarkable transcriptional activation of myeloid lineage marker genes (CD11b/ITGAM and CD86), reduction of cell proliferation and decrease of clonogenic ability of human AML cells. Cell surface expression of CD11b and CD86 is significantly and dynamically increased in human AML cells upon sustained LSD1 inhibition. Chromatin immunoprecipitation and quantitative PCR (ChIP-qPCR) analyses of histone marks revealed that there is a specific increase of H3K4me2 modification and an accompanied increase of H3K4me3 modification at the respective CD11b and CD86 promoter region, whereas the global H3K4me2 level remains constant. Consistently, inhibition of LSD1 in vivo significantly blocks tumor growth and induces a prominent increase of CD11b and CD86. Taken together, our results demonstrate the anti-tumor properties of LSD1 inhibition on human AML cell line and mouse xenograft model. Our findings provide mechanistic insights into the LSD1 functions in controlling both differentiation and proliferation in AML.


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