Cited by 294Acute Myeloid Leukemia ResearchEpigenetics and DNA MethylationRetinoids in leukemia and cellular processes

Highly effective combination of LSD1 (KDM1A) antagonist and pan-histone deacetylase inhibitor against human AML cells

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Fiskus, W, Sharma, S, Shah, B, Portier, B P, Devaraj, S G T, Liu, K, Iyer, S P, Bearss, D +1 more·2014·Leukemia

Abstract

The histone demethylase LSD1 (KDM1A) demethylates mono- and di-methylated (Me2) lysine (K) 4 on histone H3. High LSD1 expression blocks differentiation and confers a poor prognosis in acute myeloid leukemia (AML). Here, treatment with the novel LSD1 antagonist SP2509 attenuated the binding of LSD1 with the corepressor CoREST, increased the permissive H3K4Me3 mark on the target gene promoters, and increased the levels of p21, p27 and CCAAT/enhancer binding protein α in cultured AML cells. In addition, SP2509 treatment or LSD1 shRNA inhibited the colony growth of AML cells. SP2509 also induced morphological features of differentiation in the cultured and primary AML blasts. SP2509 induced more apoptosis of AML cells expressing mutant NPM1 than mixed-lineage leukemia fusion oncoproteins. Treatment with SP2509 alone significantly improved the survival of immune-depleted mice following tail-vein infusion and engraftment of cultured or primary human AML cells. Co-treatment with pan-HDAC inhibitor (HDI) panobinostat (PS) and SP2509 was synergistically lethal against cultured and primary AML blasts. Compared with each agent alone, co-treatment with SP2509 and PS significantly improved the survival of the mice engrafted with the human AML cells, without exhibiting any toxicity. Collectively, these findings show that the combination of LSD1 antagonist and pan-HDI is a promising therapy warranting further testing against AML.

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Crossref · 10.1038/leu.2014.119

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  • These findings support and provide a molecular explanation for observations that combination therapies of KDM1A antagonist and HDAC inhibitors show enhanced response.

    “These findings support and provide a molecular explanation for recent observations that combination therapies of KDM1A antagonist and HDAC inhibitors exhibit an enhanced response29.”

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Authors
Fiskus, W., Sharma, S., Shah, B., Portier, B. P., Devaraj, S. G. T., Liu, K., Iyer, S. P., Bearss, D., & Bhalla, K. N.
Affiliations
  • Houston Methodist (US)
  • University of Utah (US)
  • Brigham Young University (US)
Corresponding author
Bhalla, K N
Venue
Leukemia
Published
2014-04-04
Volume
28
Issue
11
Pages
2155-2164
ISSN
  • 0887-6924 (ISSN-L)
  • 1476-5551
OpenAlex
W2006229882
Cited by
284
References
45
Citations by year
2026: 8 · 2025: 14 · 2024: 21 · 2023: 18 · 2022: 20 · 2021: 18 · 2020: 25 · 2019: 27 · 2018: 26 · 2017: 45 · 2016: 35 · 2015: 21 · 2014: 5
FWCI
25.06
Type
journal article
Language
en
Update notices
erratum (2017-03-21)
Open access
Locations
  • Leukemia (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
National Cancer Institute (R01CA171338, R01CA173877, R01CA123207)
Topics
  • Health Sciences › Medicine › Hematology › Acute Myeloid Leukemia Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Retinoids in leukemia and cellular processes
Keywords
LSD1, acute myeloid leukemia, histone deacetylase inhibitors, panobinostat, combination therapy, H3K4 demethylation, leukemia cell differentiation, apoptosis, NPM1 mutation, MLL fusion, synergistic lethality
MeSH terms
Nucleophosmin, Animals, Cells, Cultured, Disease Models, Animal, Enzyme Inhibitors, Female, Histones, Humans, Hydrazines, Nerve Tissue Proteins, Stem Cells, Sulfonamides, Tumor Cells, Cultured, Leukemia, Myeloid, Acute, Mice, SCID, Mice, Inbred NOD, Apoptosis, Xenograft Model Antitumor Assays, RNA, Small Interfering, Histone Acetyltransferases, Histone Demethylases, Co-Repressor Proteins

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