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

Fang, Jianwu and Ying, Haiyan and Mao, Ting and Fang, Yelena and Lu, Yuan and Wang, He and Zang, Irene and Wang, Zhaofu and Lin, Ying and Zhao, Mengxi and Luo, Xiao and Wang, Zongyao and Zhang, Yan and Zhang, Chao and Wang, William and Tan, Wei and Chen, Zhui and Lu, Chris and Atadja, Peter and Li, En and Zhao, Kehao and Liu, Jianfeng and Gu, Justin (2017) Upregulation of CD11b and CD86 through LSD1 inhibition promotes myeloid differentiation promotion and suppresses cell proliferation in human monocytic leukemia cells. Oncotarget. ISSN 1949-2553

Abstract

Previous studies elucidated that 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/mouse leukemia cells. However, the pro-differentiation and anti-proliferation effects of LSD1 inhibition in infant MLL-AF9 monocytic leukemia are not fully understood yet. 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) and reduction of cell proliferation and clonogenecity of THP-1. Flow cytometry analyses show that cell surface expression of CD11b and CD86 is significantly increased in THP-1 with LSD1 inhibition. Chromatin immunoprecipitation and quantitative PCR(ChIP-qPCR) analyses of histone marks reveals that there is a specific increase of H3K4me2 modification at the CD11b promoter region, though global H3K4me2 level remains constant. Inhibition of LSD1 in vivo significantly inhibits tumor growth and causes a prominent increase of CD11b. Taken together, our results demonstrate the anti-tumor properties of LSD1 inhibition on human monocytic leukemia cell line, THP-1 and its mouse xenograft model. It provides insights into the role of LSD1 in AML.

Item Type: Article
Keywords: LSD1, CD11b, CD86, myeloid differentiation, monocytic leukemia
Date Deposited: 22 Aug 2017 00:45
Last Modified: 22 Aug 2017 00:45
URI: https://oak.novartis.com/id/eprint/31050

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