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 Advjournal_title
Science advancesauthors
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 Sdoi
10.1126/sciadv.aax2746subject
Has Abstractpub_date
2020-04-08 00:00:00pages
eaax2746issue
15issn
2375-2548pii
aax2746journal_volume
6pub_type
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