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Open Access 01-12-2016 | Research

Pharmacological inhibition of LSD1 for the treatment of MLL-rearranged leukemia

Authors: Zizhen Feng, Yuan Yao, Chao Zhou, Fengju Chen, Fangrui Wu, Liping Wei, Wei Liu, Shuo Dong, Michele Redell, Qianxing Mo, Yongcheng Song

Published in: Journal of Hematology & Oncology | Issue 1/2016

Abstract

Background

Mixed lineage leukemia (MLL) gene translocations are found in ~75 % infant and 10 % adult acute leukemia, showing a poor prognosis. Lysine-specific demethylase 1 (LSD1) has recently been implicated to be a drug target for this subtype of leukemia. More studies using potent LSD1 inhibitors against MLL-rearranged leukemia are needed.

Methods

LSD1 inhibitors were examined for their biochemical and biological activities against LSD1 and MLL-rearranged leukemia as well as other cancer cells.

Results

Potent LSD1 inhibitors with biochemical IC₅₀ values of 9.8–77 nM were found to strongly inhibit proliferation of MLL-rearranged leukemia cells with EC₅₀ of 10–320 nM, while these compounds are generally non-cytotoxic to several other tumor cells. LSD1 inhibition increased histone H3 lysine 4 (H3K4) methylation, downregulated expression of several leukemia-relevant genes, induced apoptosis and differentiation, and inhibited self-renewal of stem-like leukemia cells. Moreover, LSD1 inhibitors worked synergistically with inhibition of DOT1L, a histone H3 lysine 79 (H3K79) methyltransferase, against MLL-rearranged leukemia. The most potent LSD1 inhibitor showed significant in vivo activity in a systemic mouse model of MLL-rearranged leukemia without overt toxicities. Mechanistically, LSD1 inhibitors caused significant upregulation of several pathways that promote hematopoietic differentiation and apoptosis.

Conclusions

LSD1 is a drug target for MLL-rearranged leukemia, and LSD1 inhibitors are potential therapeutics for the malignancy.

Available only for authorised users

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Title: Pharmacological inhibition of LSD1 for the treatment of MLL-rearranged leukemia
Authors: Zizhen Feng
Yuan Yao
Chao Zhou
Fengju Chen
Fangrui Wu
Liping Wei
Wei Liu
Shuo Dong
Michele Redell
Qianxing Mo
Yongcheng Song
Publication date: 01-12-2016
Publisher: BioMed Central
Published in: Journal of Hematology & Oncology / Issue 1/2016
Electronic ISSN: 1756-8722
DOI: https://doi.org/10.1186/s13045-016-0252-7

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Abstract

Background

Methods

Results

Conclusions

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