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

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 inhibitor...

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Detalles Bibliográficos
Autores principales: Feng, Zizhen, Yao, Yuan, Zhou, Chao, Chen, Fengju, Wu, Fangrui, Wei, Liping, Liu, Wei, Dong, Shuo, Redell, Michele, Mo, Qianxing, Song, Yongcheng
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4789278/
https://www.ncbi.nlm.nih.gov/pubmed/26970896
http://dx.doi.org/10.1186/s13045-016-0252-7
Descripción
Sumario: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 IC(50) values of 9.8–77 nM were found to strongly inhibit proliferation of MLL-rearranged leukemia cells with EC(50) 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. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s13045-016-0252-7) contains supplementary material, which is available to authorized users.