Enhancer activation by pharmacologic displacement of LSD1 from GFI1 induces differentiation in acute myeloid leukemia.
Name:
S2211-1247(18)30341-3.pdf
Size:
3.734Mb
Format:
PDF
Description:
Open access full text article
Authors
Maiques-Diaz, AlbaSpencer, Gary J
Lynch, James T
Ciceri, Filippo
Williams, Emma L
Amaral, Fabio
Wiseman, Daniel H
Harris, William J
Li, Yaoyong
Sahoo, Sudhakar
Hitchin, James R
Mould, Daniel P
Fairweather, Emma E
Waszkowycz, Bohdan
Jordan, Allan M
Smith, Duncan L
Somervaille, Tim CP
Affiliation
Leukaemia Biology Laboratory, Cancer Research UK Manchester Institute, The University of Manchester, Manchester Cancer Research Centre Building, 555 Wilmslow Road, Manchester M20 4GJ,Issue Date
2018-03-27
Metadata
Show full item recordAbstract
Pharmacologic inhibition of LSD1 promotes blast cell differentiation in acute myeloid leukemia (AML) with MLL translocations. The assumption has been that differentiation is induced through blockade of LSD1's histone demethylase activity. However, we observed that rapid, extensive, drug-induced changes in transcription occurred without genome-wide accumulation of the histone modifications targeted for demethylation by LSD1 at sites of LSD1 binding and that a demethylase-defective mutant rescued LSD1 knockdown AML cells as efficiently as wild-type protein. Rather, LSD1 inhibitors disrupt the interaction of LSD1 and RCOR1 with the SNAG-domain transcription repressor GFI1, which is bound to a discrete set of enhancers located close to transcription factor genes that regulate myeloid differentiation. Physical separation of LSD1/RCOR1 from GFI1 is required for drug-induced differentiation. The consequent inactivation of GFI1 leads to increased enhancer histone acetylation within hours, which directly correlates with the upregulation of nearby subordinate genes.Citation
Enhancer activation by pharmacologic displacement of LSD1 from GFI1 induces differentiation in acute myeloid leukemia. 2018, 22(13): 3641-3659 Cell RepJournal
Cell ReportsDOI
10.1016/j.celrep.2018.03.012PubMed ID
29590629Type
ArticleLanguage
enISSN
2211-1247ae974a485f413a2113503eed53cd6c53
10.1016/j.celrep.2018.03.012
Scopus Count
Collections
Related articles
- HMG20B stabilizes association of LSD1 with GFI1 on chromatin to confer transcription repression and leukemia cell differentiation block.
- Authors: Maiques-Diaz A, Nicosia L, Basma NJ, Romero-Camarero I, Camera F, Spencer GJ, Amaral FMR, Simeoni F, Wingelhofer B, Williamson AJK, Pierce A, Whetton AD, Somervaille TCP
- Issue date: 2022 Oct
- LSD1 inhibition by tranylcypromine derivatives interferes with GFI1-mediated repression of PU.1 target genes and induces differentiation in AML.
- Authors: Barth J, Abou-El-Ardat K, Dalic D, Kurrle N, Maier AM, Mohr S, Schütte J, Vassen L, Greve G, Schulz-Fincke J, Schmitt M, Tosic M, Metzger E, Bug G, Khandanpour C, Wagner SA, Lübbert M, Jung M, Serve H, Schüle R, Berg T
- Issue date: 2019 Jun
- Nascent transcript and single-cell RNA-seq analysis defines the mechanism of action of the LSD1 inhibitor INCB059872 in myeloid leukemia.
- Authors: Johnston G, Ramsey HE, Liu Q, Wang J, Stengel KR, Sampathi S, Acharya P, Arrate M, Stubbs MC, Burn T, Savona MR, Hiebert SW
- Issue date: 2020 Aug 20
- Targeting the scaffolding role of LSD1 (KDM1A) poises acute myeloid leukemia cells for retinoic acid-induced differentiation.
- 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
- Issue date: 2020 Apr
- LSD1-mediated repression of GFI1 super-enhancer plays an essential role in erythroleukemia.
- Authors: Tatsumi G, Kawahara M, Yamamoto R, Hishizawa M, Kito K, Suzuki T, Takaori-Kondo A, Andoh A
- Issue date: 2020 Mar