Targeting the Scaffolding Role of LSD1 (KDM1A) Poises Acute Myeloid Leukemia Cells for Retinoic Acid-induced Differentiation

Overview

Journal Sci Adv

Specialties Biology
Science

Date 2020 Apr 15

PMID 32284990

Citations 34

Authors

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

Affiliations

Soon will be listed here.

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.

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