ArticleJournal of hematology & oncology2016
Pharmacological inhibition of LSD1 for the treatment of MLL-rearranged leukemia.
Article in Journal of hematology & oncology, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 65 papers.
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Who cites it
65 citing papers in PubMed, 104 citations in OpenAlex.
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- Lysine methylation modifications in tumor immunomodulation and immunotherapy: regulatory mechanisms and perspectives.Biomarker research · 2024Review
- Induction of AML cell differentiation using HOXA9/DNA binding inhibitors as a potential therapeutic option for HOXA9-dependent AML.HemaSphere · 2024Article
- Novel insights into histone lysine methyltransferases in cancer therapy: From epigenetic regulation to selective drugs.Journal of pharmaceutical analysis · 2023Review
- Targeting LSD1 in tumor immunotherapy: rationale, challenges and potential.Frontiers in immunology · 2023Review
- Advances in molecular characterization of pediatric acute megakaryoblastic leukemia not associated with Down syndrome; impact on therapy development.Frontiers in cell and developmental biology · 2023Review
- Novel dual LSD1/HDAC6 inhibitor for the treatment of cancer.PloS one · 2023Article
- Epigenetic targets in B- and T-cell lymphomas: latest developments.Therapeutic advances in hematology · 2023Review
- Melatonin as a regulator of apoptosis in leukaemia: molecular mechanism and therapeutic perspectives.Frontiers in pharmacology · 2023Review
- Epimutations and Their Effect on Chromatin Organization: Exciting Avenues for Cancer Treatment.Cancers · 2022Review
- Structure-activity relationship and antitumor activity of 1,4-pyrazine-containing inhibitors of histone acetyltransferases P300/CBP.European journal of medicinal chemistry · 2022Article
- A proteolysis-targeting chimera molecule selectively degrades ENL and inhibits malignant gene expression and tumor growth.Journal of hematology & oncology · 2022Article
- Targeting the histone H3 lysine 79 methyltransferase DOT1L in MLL-rearranged leukemias.Journal of hematology & oncology · 2022Review
- SALL4 Oncogenic Function in Cancers: Mechanisms and Therapeutic Relevance.International journal of molecular sciences · 2022Review
- Mechanisms of carcinogenic activity triggered by lysine-specific demethylase 1A.Frontiers in pharmacology · 2022Review
- Discovery of orally active chalcones as histone lysine specific demethylase 1 inhibitors for the treatment of leukaemia.Journal of enzyme inhibition and medicinal chemistry · 2021Article
5 more citing papers are in PubMed but not listed here.
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Authors and funding
11 authors at 1 institution in 1 country.
Funding
Abstract
backgroundMixed 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.
methodsLSD1 inhibitors were examined for their biochemical and biological activities against LSD1 and MLL-rearranged leukemia as well as other cancer cells.
resultsPotent 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.
conclusionsLSD1 is a drug target for MLL-rearranged leukemia, and LSD1 inhibitors are potential therapeutics for the malignancy.
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