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

Roberto Ravasio, Elena Ceccacci, Luciano Nicosia, Amir Hosseini, Pier Luigi Rossi, Iros Barozzi, Lorenzo Fornasari, Roberto Dal Zuffo, Sergio Valente, Rossella Fioravanti, Ciro Mercurio, Mario Varasi, Andrea Mattevi, Antonello Mai, Giulio Pavesi, Tiziana Bonaldi, Saverio Minucci

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish
Article numbereaax2746
JournalScience advances
Volume6
Issue number15
DOIs
Publication statusPublished - 2020

ASJC Scopus subject areas

  • General

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