The online version of this article (doi:10.1186/s13045-016-0252-7) contains supplementary material, which is available to authorized users.
The authors declare that they have no competing interests.
ZF designed the experiments, performed most of the biological activity testing, analyzed data, and provided figures. YY did the antiproliferation assays and analyzed data. CZ and LW synthesized and characterized all compounds. FW performed the biochemical assays and analyzed data. WL and MR did the colony-forming assay of patient-derived samples. FC and QM performed the microarray data analysis and provided figures. SD performed the data analysis. YS conceived the project, designed the experiments, analyzed data, and wrote the manuscript. All authors read and approved the final manuscript.
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.
LSD1 inhibitors were examined for their biochemical and biological activities against LSD1 and MLL-rearranged leukemia as well as other cancer cells.
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.
LSD1 is a drug target for MLL-rearranged leukemia, and LSD1 inhibitors are potential therapeutics for the malignancy.
Additional file 1: Figures S1-S7, Table S1 and Compound synthesis and characterization. (PDF 1450 kb)13045_2016_252_MOESM1_ESM.pdf
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- Pharmacological inhibition of LSD1 for the treatment of MLL-rearranged leukemia
- BioMed Central
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