Targeting the scaffolding role of LSD1 (KDM1A) poises acute myeloid leukemia cells for retinoic acid–induced differentiation

Autor: Luciano Nicosia, Amir Hosseini, Roberto Ravasio, Mario Varasi, Elena Ceccacci, Iros Barozzi, Roberto Dal Zuffo, Pier Luigi Rossi, Antonello Mai, Andrea Mattevi, Lorenzo Fornasari, Giulio Pavesi, Sergio Valente, Tiziana Bonaldi, Rossella Fioravanti, Saverio Minucci, Ciro Mercurio
Jazyk: angličtina
Rok vydání: 2020
Předmět:
Oncogene Proteins
Fusion
Retinoic acid
Histones
chemistry.chemical_compound
0302 clinical medicine
Leukemia
Promyelocytic
Acute
hemic and lymphatic diseases
Tumor Cells
Cultured
Research Articles
Cancer
Epigenomics
Histone Demethylases
0303 health sciences
Multidisciplinary
biology
Chemistry
SciAdv r-articles
Myeloid leukemia
Cell Differentiation
inhibition
Chromatin
Leukemia
Myeloid
Acute
030220 oncology & carcinogenesis
reveals
Research Article
Acute promyelocytic leukemia
animal structures
Antineoplastic Agents
Tretinoin
Catalysis
corest
03 medical and health sciences
gfi1
Cell Line
Tumor
medicine
Humans
LSD1 leukemia
acute promyelocytic leukemia
proteins
quantification
recruitment
activation
neoplasms
030304 developmental biology
Dose-Response Relationship
Drug
Oncogene
KDM1A
medicine.disease
Drug Resistance
Neoplasm
Cancer research
biology.protein
Demethylase
Zdroj: Science Advances
Popis: The study addresses the mechanism through which inhibition of LSD1 sensitizes AML cells to retinoic acid–induced differentiation.
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.
Databáze: OpenAIRE
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