Targeting the scaffolding role of LSD1 (KDM1A) poises acute myeloid leukemia cells for retinoic acid-induced differentiation.
Antineoplastic Agents
/ pharmacology
Catalysis
Cell Differentiation
/ drug effects
Cell Line, Tumor
Dose-Response Relationship, Drug
Drug Resistance, Neoplasm
Histone Demethylases
/ antagonists & inhibitors
Histones
/ metabolism
Humans
Leukemia, Myeloid, Acute
/ drug therapy
Leukemia, Promyelocytic, Acute
Oncogene Proteins, Fusion
/ genetics
Tretinoin
/ pharmacology
Tumor Cells, Cultured
Journal
Science advances
ISSN: 2375-2548
Titre abrégé: Sci Adv
Pays: United States
ID NLM: 101653440
Informations de publication
Date de publication:
04 2020
04 2020
Historique:
received:
08
03
2019
accepted:
15
01
2020
entrez:
15
4
2020
pubmed:
15
4
2020
medline:
16
12
2020
Statut:
epublish
Résumé
The histone demethylase LSD1 is deregulated in several tumors, including leukemias, providing the rationale for the clinical use of LSD1 inhibitors. In acute promyelocytic leukemia (APL), pharmacological doses of retinoic acid (RA) induce differentiation of APL cells, triggering degradation of the PML-RAR oncogene. APL cells are resistant to LSD1 inhibition or knockout, but targeting LSD1 sensitizes them to physiological doses of RA without altering of PML-RAR levels, and extends survival of leukemic mice upon RA treatment. The combination of RA with LSD1 inhibition (or knockout) is also effective in other non-APL, acute myeloid leukemia (AML) cells. Nonenzymatic activities of LSD1 are essential to block differentiation, while RA with targeting of LSD1 releases a differentiation gene expression program, not strictly dependent on changes in histone H3K4 methylation. Integration of proteomic/epigenomic/mutational studies showed that LSD1 inhibitors alter the recruitment of LSD1-containing complexes to chromatin, inhibiting the interaction between LSD1 and the transcription factor GFI1.
Identifiants
pubmed: 32284990
doi: 10.1126/sciadv.aax2746
pii: aax2746
pmc: PMC7141832
doi:
Substances chimiques
Antineoplastic Agents
0
Histones
0
Oncogene Proteins, Fusion
0
PML-RARa bcr1 fusion protein, human
0
Tretinoin
5688UTC01R
Histone Demethylases
EC 1.14.11.-
KDM1A protein, human
EC 1.5.-
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
eaax2746Informations de copyright
Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC).
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