Enhancer activation by pharmacologic displacement of LSD1 from GFI1 induces differentiation in acute myeloid leukemia

Alba Maiques-Diaz, Gary Spencer, James Lynch, Filippo Ciceri, Emma Williams, Fabio Amaral, Daniel Wiseman, Yaoyong Li, Sudhakar Sahoo, James Hitchin, Daniel Mould, Emma Fairweather, Bohdan Waszkowycz, Allan Jordan, Duncan Smith, Timothy Somervaille

Research output: Contribution to journalArticlepeer-review


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 which 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 up regulation of nearby, subordinate genes.
Original languageEnglish
Pages (from-to)3641-3659
Number of pages19
JournalCell Reports
Issue number13
Early online date27 Mar 2018
Publication statusPublished - 27 Mar 2018


  • GFI1
  • LSD1
  • MLL
  • acetylation
  • acute myeloid leukemia
  • methylation

Research Beacons, Institutes and Platforms

  • Manchester Cancer Research Centre


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