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

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.

• Authors: Zizhen Feng, Yuan Yao, Chao Zhou, Fengju Chen, Fangrui Wu, Liping Wei, Wei Liu, Shuo Dong, Michele Redell, Qianxing Mo, Yongcheng Song
• Journal: Journal of hematology & oncology (J Hematol Oncol) Vol. 9 Pg. 24 (Mar 12 2016) ISSN: 1756-8722 [Electronic] England
• PMID: 26970896 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Enzyme Inhibitors
• Histones
• KMT2A protein, human
• Monoamine Oxidase Inhibitors
• Myeloid-Lymphoid Leukemia Protein
• Histone Demethylases
• KDM1A protein, human
• DOT1L protein, human
• Methyltransferases
• Histone-Lysine N-Methyltransferase
• Lysine

Topics

• Animals
• Blotting, Western
• Cell Line, Tumor
• Cell Proliferation (drug effects, genetics)
• Child
• Drug Synergism
• Enzyme Inhibitors (chemistry, pharmacology)
• Gene Expression Regulation, Leukemic (drug effects)
• Gene Rearrangement
• Histone Demethylases (antagonists & inhibitors, genetics, metabolism)
• Histone-Lysine N-Methyltransferase (genetics)
• Histones (metabolism)
• Humans
• Leukemia (drug therapy, genetics, metabolism)
• Lysine (metabolism)
• MCF-7 Cells
• Methylation (drug effects)
• Methyltransferases (antagonists & inhibitors, genetics, metabolism)
• Mice, Inbred NOD
• Mice, SCID
• Molecular Structure
• Monoamine Oxidase Inhibitors (chemistry, pharmacology)
• Myeloid-Lymphoid Leukemia Protein (genetics)
• Reverse Transcriptase Polymerase Chain Reaction
• U937 Cells
• Xenograft Model Antitumor Assays