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

Subramaniam, Agatheeswaran LU ; Zemaitis, Kristijonas LU ; Safaee Talkhoncheh, Mehrnaz LU ; Yudovich, David LU ; Bäckström, Alexandra LU ; Debnath, Shubhranshu LU ; Chen, Jun LU ; Jain, Mayur Vilas LU ; Galeev, Roman LU and Gaetani, Massimiliano , et al. (2020) In Blood 136(19). p.2151-2161
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... (More)

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.

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organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Blood
volume
136
issue
19
pages
11 pages
publisher
American Society of Hematology
external identifiers
  • pmid:32582923
  • scopus:85095862481
ISSN
1528-0020
DOI
10.1182/blood.2020005827
language
English
LU publication?
yes
additional info
Copyright © 2020 American Society of Hematology.
id
3308a54c-1536-49df-9446-e9cc11d8f37d
date added to LUP
2020-07-06 23:57:10
date last changed
2024-04-03 07:52:09
@article{3308a54c-1536-49df-9446-e9cc11d8f37d,
  abstract     = {{<p>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.</p>}},
  author       = {{Subramaniam, Agatheeswaran and Zemaitis, Kristijonas and Safaee Talkhoncheh, Mehrnaz and Yudovich, David and Bäckström, Alexandra and Debnath, Shubhranshu and Chen, Jun and Jain, Mayur Vilas and Galeev, Roman and Gaetani, Massimiliano and Zubarev, Roman A and Larsson, Jonas}},
  issn         = {{1528-0020}},
  language     = {{eng}},
  month        = {{11}},
  number       = {{19}},
  pages        = {{2151--2161}},
  publisher    = {{American Society of Hematology}},
  series       = {{Blood}},
  title        = {{Lysine-specific demethylase 1A (LSD1) restricts ex vivo propagation of human HSCs and is a target of UM171}},
  url          = {{http://dx.doi.org/10.1182/blood.2020005827}},
  doi          = {{10.1182/blood.2020005827}},
  volume       = {{136}},
  year         = {{2020}},
}