BET inhibitors impair leukemic stem cell function only in defined oncogenic subgroups of acute myeloid leukaemias

Leuk Res. 2019 Dec:87:106269. doi: 10.1016/j.leukres.2019.106269. Epub 2019 Nov 7.

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.

Keywords: Acute myeloid leukaemia; BET bromodomains; Leukemic stem cells; Long term culture; MLL partial tandem duplication.

Publication types

  • Letter
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacology*
  • Antineoplastic Agents / therapeutic use
  • Bromodomain Containing Proteins
  • Hematopoietic Stem Cell Transplantation
  • Humans
  • Leukemia, Myeloid, Acute / genetics*
  • Leukemia, Myeloid, Acute / pathology*
  • Leukemia, Myeloid, Acute / therapy
  • Mice
  • Mice, Transgenic
  • Mutation
  • Neoplasm Staging
  • Neoplastic Stem Cells / drug effects*
  • Neoplastic Stem Cells / pathology
  • Neoplastic Stem Cells / physiology
  • Nucleophosmin
  • Oncogenes / genetics
  • Proteins / antagonists & inhibitors*
  • Proteins / genetics
  • Treatment Outcome
  • Tumor Cells, Cultured
  • Xenograft Model Antitumor Assays

Substances

  • Antineoplastic Agents
  • Nucleophosmin
  • Proteins
  • NPM1 protein, human
  • Npm1 protein, mouse
  • bromodomain and extra-terminal domain protein, human
  • Bromodomain Containing Proteins