Lysine-specific demethylase 1A (LSD1) restricts ex vivo propagation of human HSCs and is a target of UM171

Research output: Contribution to journalArticle

Abstract

Culture conditions in which hematopoietic stem cells (HSCs) can be expanded for clinical benefit are highly sought after. Here, we report that inhibition of the epigenetic regulator Lysine-specific histone demethylase 1A (LSD1) induces a rapid expansion of human cord blood derived CD34+ cells and promotes in vitro propagation of long-term repopulating HSCs by preventing differentiation. The phenotype and molecular characteristics of cells treated with LSD1 inhibitors were highly similar to cells treated with UM171, an agent promoting expansion of HSCs through undefined mechanisms, and currently tested in clinical trials. Strikingly, we found that LSD1 as well as other members of the LSD1 containing chromatin remodeling complex CoREST are rapidly poly-ubiquitinated and degraded upon UM171 treatment. CRISPR/Cas9 depletion of the CoREST core member, RCOR1, resulted in expansion of CD34+ cells similar to LSD1 inhibition and UM171. Taken together, LSD1 and CoREST restrict HSC expansion, and are principal targets of UM171, forming a mechanistic basis for the HSC promoting activity of UM171.

Details

Authors
Organisations
External organisations
  • Karolinska Institutet
  • Science for Life Laboratory (SciLifeLab)
Research areas and keywords

Subject classification (UKÄ) – MANDATORY

  • Cell and Molecular Biology
  • Hematology
Original languageEnglish
Pages (from-to)2151-2161
Number of pages11
JournalBlood
Volume136
Issue number19
Early online date2020 Jun 24
Publication statusPublished - 2020 Nov 5
Publication categoryResearch
Peer-reviewedYes

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Copyright © 2020 American Society of Hematology.