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

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.

journal_name

Sci Adv

journal_title

Science advances

authors

Ravasio R,Ceccacci E,Nicosia L,Hosseini A,Rossi PL,Barozzi I,Fornasari L,Zuffo RD,Valente S,Fioravanti R,Mercurio C,Varasi M,Mattevi A,Mai A,Pavesi G,Bonaldi T,Minucci S

doi

10.1126/sciadv.aax2746

subject

Has Abstract

pub_date

2020-04-08 00:00:00

pages

eaax2746

issue

15

issn

2375-2548

pii

aax2746

journal_volume

6

pub_type

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