Lysine-specific Demethylase 1A Restricts Ex Vivo Propagation of Human HSCs and is a Target of UM171

Overview

Journal Blood

Publisher Elsevier

Specialty Hematology

Date 2020 Jun 26

PMID 32582923

Citations 30

Authors

Agatheeswaran Subramaniam

Kristijonas Zemaitis

Mehrnaz Safaee Talkhoncheh

David Yudovich

Alexandra Backstrom

Shubhranshu Debnath

Jun Chen

Mayur Vilas Jain

Roman Galeev

Massimiliano Gaetani

Roman A Zubarev

Jonas Larsson

Affiliations

Soon will be listed here.

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 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.

Citing Articles

Molecular glue unexpectedly mimics the effect of cancer mutations.

Bushman J, Potts P Nature. 2025; 639(8053):42-43.

PMID: 39966588 DOI: 10.1038/d41586-025-00090-7.

UM171 glues asymmetric CRL3-HDAC1/2 assembly to degrade CoREST corepressors.

Yeo M, Zhang O, Xie X, Nam E, Payne N, Gosavi P Nature. 2025; 639(8053):232-240.

PMID: 39939761 PMC: 11882444. DOI: 10.1038/s41586-024-08532-4.

Deciphering the effect of UM171 on human hematopoietic progenitor cell fate through clonal analysis.

Coulombe P, Tomellini E, Chagraoui J, Mayotte N, Sauvageau G Nat Commun. 2025; 16(1):195.

PMID: 39747844 PMC: 11696577. DOI: 10.1038/s41467-024-55225-7.

Modification of Lhx2 activity for amplification of human iPSC-derived hematopoietic stem/progenitor cells.

Kitajima K, Takahashi Y, Ando H, Shingai M, Hamasaki M, Tanikawa M Front Cell Dev Biol. 2024; 12:1482989.

PMID: 39474350 PMC: 11518812. DOI: 10.3389/fcell.2024.1482989.

UM171 enhances fitness and engraftment of gene-modified hematopoietic stem cells from patients with sickle cell disease.

Liu B, Klatt D, Zhou Y, Manis J, Sauvageau G, Pellin D Blood Adv. 2024; 8(22):5885-5895.

PMID: 39293082 PMC: 11612367. DOI: 10.1182/bloodadvances.2024013932.

References

Laurenti E, Doulatov S, Zandi S, Plumb I, Chen J, April C . The transcriptional architecture of early human hematopoiesis identifies multilevel control of lymphoid commitment. Nat Immunol. 2013; 14(7):756-63. PMC: 4961471. DOI: 10.1038/ni.2615. View

Srour E, Tong X, Sung K, Plett P, Rice S, Daggy J . Modulation of in vitro proliferation kinetics and primitive hematopoietic potential of individual human CD34+CD38-/lo cells in G0. Blood. 2004; 105(8):3109-16. DOI: 10.1182/blood-2004-05-1773. View

Norkin M, Lazarus H, Wingard J . Umbilical cord blood graft enhancement strategies: has the time come to move these into the clinic?. Bone Marrow Transplant. 2012; 48(7):884-9. DOI: 10.1038/bmt.2012.163. View

Irizarry R, Hobbs B, Collin F, Beazer-Barclay Y, Antonellis K, Scherf U . Exploration, normalization, and summaries of high density oligonucleotide array probe level data. Biostatistics. 2003; 4(2):249-64. DOI: 10.1093/biostatistics/4.2.249. View

Fares I, Chagraoui J, Gareau Y, Gingras S, Ruel R, Mayotte N . Cord blood expansion. Pyrimidoindole derivatives are agonists of human hematopoietic stem cell self-renewal. Science. 2014; 345(6203):1509-12. PMC: 4372335. DOI: 10.1126/science.1256337. View

Yao H, Goldman D, Nechiporuk T, Kawane S, McWeeney S, Tyner J . Corepressor Rcor1 is essential for murine erythropoiesis. Blood. 2014; 123(20):3175-84. PMC: 4023423. DOI: 10.1182/blood-2013-11-538678. View

Boitano A, Wang J, Romeo R, Bouchez L, Parker A, Sutton S . Aryl hydrocarbon receptor antagonists promote the expansion of human hematopoietic stem cells. Science. 2010; 329(5997):1345-8. PMC: 3033342. DOI: 10.1126/science.1191536. View

Franken H, Mathieson T, Childs D, Sweetman G, Werner T, Togel I . Thermal proteome profiling for unbiased identification of direct and indirect drug targets using multiplexed quantitative mass spectrometry. Nat Protoc. 2015; 10(10):1567-93. DOI: 10.1038/nprot.2015.101. View

Fares I, Chagraoui J, Lehnertz B, MacRae T, Mayotte N, Tomellini E . EPCR expression marks UM171-expanded CD34 cord blood stem cells. Blood. 2017; 129(25):3344-3351. DOI: 10.1182/blood-2016-11-750729. View

10.

Prashad S, Calvanese V, Yao C, Kaiser J, Wang Y, Sasidharan R . GPI-80 defines self-renewal ability in hematopoietic stem cells during human development. Cell Stem Cell. 2014; 16(1):80-7. PMC: 4520393. DOI: 10.1016/j.stem.2014.10.020. View

11.

Hu Y, Smyth G . ELDA: extreme limiting dilution analysis for comparing depleted and enriched populations in stem cell and other assays. J Immunol Methods. 2009; 347(1-2):70-8. DOI: 10.1016/j.jim.2009.06.008. View

12.

Lee M, Wynder C, Schmidt D, McCafferty D, Shiekhattar R . Histone H3 lysine 4 demethylation is a target of nonselective antidepressive medications. Chem Biol. 2006; 13(6):563-7. DOI: 10.1016/j.chembiol.2006.05.004. View

13.

Rudolph T, Beuch S, Reuter G . Lysine-specific histone demethylase LSD1 and the dynamic control of chromatin. Biol Chem. 2013; 394(8):1019-28. DOI: 10.1515/hsz-2013-0119. View

14.

North T, Goessling W, Walkley C, Lengerke C, Kopani K, Lord A . Prostaglandin E2 regulates vertebrate haematopoietic stem cell homeostasis. Nature. 2007; 447(7147):1007-11. PMC: 2775137. DOI: 10.1038/nature05883. View

15.

Doulatov S, Vo L, Chou S, Kim P, Arora N, Li H . Induction of multipotential hematopoietic progenitors from human pluripotent stem cells via respecification of lineage-restricted precursors. Cell Stem Cell. 2013; 13(4):459-70. PMC: 3888026. DOI: 10.1016/j.stem.2013.09.002. View

16.

Kronke J, Udeshi N, Narla A, Grauman P, Hurst S, McConkey M . Lenalidomide causes selective degradation of IKZF1 and IKZF3 in multiple myeloma cells. Science. 2013; 343(6168):301-5. PMC: 4077049. DOI: 10.1126/science.1244851. View

17.

Metzger E, Wissmann M, Yin N, Muller J, Schneider R, Peters A . LSD1 demethylates repressive histone marks to promote androgen-receptor-dependent transcription. Nature. 2005; 437(7057):436-9. DOI: 10.1038/nature04020. View

18.

Baudet A, Karlsson C, Safaee Talkhoncheh M, Galeev R, Magnusson M, Larsson J . RNAi screen identifies MAPK14 as a druggable suppressor of human hematopoietic stem cell expansion. Blood. 2012; 119(26):6255-8. DOI: 10.1182/blood-2012-01-403949. View

19.

Cox J, Mann M . MaxQuant enables high peptide identification rates, individualized p.p.b.-range mass accuracies and proteome-wide protein quantification. Nat Biotechnol. 2008; 26(12):1367-72. DOI: 10.1038/nbt.1511. View

20.

Lee M, Wynder C, Cooch N, Shiekhattar R . An essential role for CoREST in nucleosomal histone 3 lysine 4 demethylation. Nature. 2005; 437(7057):432-5. DOI: 10.1038/nature04021. View