4.7 Article

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

Journal

BLOOD
Volume 136, Issue 19, Pages 2151-2161

Publisher

AMER SOC HEMATOLOGY
DOI: 10.1182/blood.2020005827

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Funding

  1. Swedish Research Council
  2. Swedish Cancer Foundation
  3. Swedish Pediatric Cancer Foundation
  4. Knut och Alice Wallenbergs Stiftelse
  5. European Research Council under the European Union's Horizon 2020 research and innovation program [648894]
  6. HematoLinne and StemTherapy programs at Lund University
  7. Lady Tata Memorial Trust
  8. European Research Council (ERC) [648894] Funding Source: European Research Council (ERC)

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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 being tested in clinical trials. Strikingly, we found that LSD1, as well as other members of the LSD1-containing chromatin remodeling complex CoREST, is rapidly polyubiquitinated and degraded upon UM171 treatment. CRISPR (clustered regularly interspaced short palindromic repeats)/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.

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