TY - JOUR
T1 - Targeting the scaffolding role of LSD1 (KDM1A) poises acute myeloid leukemia cells for retinoic acid-induced differentiation
AU - Ravasio, Roberto
AU - Ceccacci, Elena
AU - Nicosia, Luciano
AU - Hosseini, Amir
AU - Rossi, Pier Luigi
AU - Barozzi, Iros
AU - Fornasari, Lorenzo
AU - Zuffo, Roberto Dal
AU - Valente, Sergio
AU - Fioravanti, Rossella
AU - Mercurio, Ciro
AU - Varasi, Mario
AU - Mattevi, Andrea
AU - Mai, Antonello
AU - Pavesi, Giulio
AU - Bonaldi, Tiziana
AU - Minucci, Saverio
N1 - Funding Information:
This work was supported by AIRC (grant number no. 19086), CNR Flagship Program EPIGEN, and TRANSCAN DRAMA project JTC 2014-48. Research in T.B.'s group was supported by AIRC (grant number 15741) and CNR Flagship Program EPIGEN. Research in A.Mat.'s laboratory was supported by AIRC (IG-11342) and MIUR (Flagship EPIGEN project and PRIN 20152TE5PK). Research in A. Mai's group was supported by AIRC (grant no. IG16 19162), MIUR (PRIN 20152TE5PK), and the Italian Ministry of Health (RF-2010-2318330).
Publisher 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).
Copyright:
Copyright 2020 Elsevier B.V., All rights reserved.
PY - 2020
Y1 - 2020
N2 - 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.
AB - 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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U2 - 10.1126/sciadv.aax2746
DO - 10.1126/sciadv.aax2746
M3 - Article
C2 - 32284990
AN - SCOPUS:85083269142
VL - 6
JO - Science advances
JF - Science advances
SN - 2375-2548
IS - 15
M1 - eaax2746
ER -