Fang, Jianwu, Ying, Haiyan, Mao, Ting, Fang, Yelena, Lu, Yuan, Wang, He, Zang, Irene, Wang, Zhaofu, Lin, Ying, Zhao, Mengxi, Luo, Xiao, Wang, Zongyao, Zhang, Yan, Zhang, Chao, Wang, William, Tan, Wei, Chen, Zhui, Lu, Chris, Atadja, Peter, Li, En, Zhao, Kehao, 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