BET inhibitors impair leukemic stem cell function only in defined oncogenic subgroups of acute myeloid leukaemias. (December 2019)

• Record Type: Journal Article
• Authors: Massé, Aline; Roulin, Louise; Pasanisi, Justine; Penneroux, Justine; Gachet, Stéphanie; Delord, Marc; Ali, Ashfaq; Alberdi, Antonio; Berrou, Jeannig; Passet, Marie; Hernandez, Lucie; Quentin, Samuel; Gardin, Claude; Raffoux, Emmanuel; Adès, Lionel; Braun, Thorsten; Soulier, Jean; Clappier, Emmanuelle; Dombret, Hervé; Puissant, Alexandre; Itzykson, Raphael
• Is Part Of: Leukemia research. Volume 87(2019)
• Publication Date: 2019-12
• Subjects: BET bromodomains -- Leukemic stem cells -- Acute myeloid leukaemia -- MLL partial tandem duplication -- Long term culture; Leukemia -- Periodicals; Leukemia -- Periodicals; Leucémie -- Périodiques; Leukemia; Periodicals; Electronic journals; Electronic journals; 616.9941905
• DOI: 10.1016/j.leukres.2019.106269
• Languages: English
• ISSNs: 0145-2126

Abstract

Abstract: Bromodomain and Extra-Terminal inhibitors (BETi) such as OTX015 are active in Acute Myeloid Leukaemias (AML). Their activity on Leukemic Stem Cells (LSCs) is less documented. We interrogated the anti-LSC activity of OTX015 in a niche-like long-term culture in 26 primary AML samples and validated our findings in vivo. OTX015 impaired LSCs in AMLs harbouring Core Binding Factor or KMT2A gene fusions, NPM1 or chromatin/spliceosome genes mutations, but not in those with aneuploidy/TP53 mutations. In four patients, we dissected the transcriptomic footprint of Bet inhibition on LSCs versus blasts. Our results can instruct future clinical trials of BETi in AML.