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Lysine-specific demethylase 1 restricts hematopoietic progenitor proliferation and is essential for terminal differentiation

A Sprüssel, JH Schulte, S Weber, M Necke, K Händschke, T Thor, KW Pajtler, A Schramm, K König and L Diehl, et al. (2012) LEUKEMIA. 26(9). p.2039-2051
abstract
Lysine (K)-specific demethylase 1A (LSD1/KDM1A) has been identified as a potential therapeutic target in solid cancers and more recently in acute myeloid leukemia. However, the potential side effects of a LSD1-inhibitory therapy remain elusive. Here, we show, with a newly established conditional in vivo knockdown model, that LSD1 represents a central regulator of hematopoietic stem and progenitor cells. LSD1 knockdown (LSD1-kd) expanded progenitor numbers by enhancing their proliferative behavior. LSD1-kd led to an extensive expansion of granulomonocytic, erythroid and megakaryocytic progenitors. In contrast, terminal granulopoiesis, erythropoiesis and platelet production were severely inhibited. The only exception was monopoiesis, which was promoted by LSD1 deficiency. Importantly, we showed that peripheral blood granulocytopenia, monocytosis, anemia and thrombocytopenia were reversible after LSD1-kd termination. Extramedullary splenic hematopoiesis contributed to the phenotypic reversion, and progenitor populations remained expanded. LSD1-kd was associated with the upregulation of key hematopoietic genes, including Gfi1b, Hoxa9 and Meis1, which are known regulators of the HSC/progenitor compartment. We also demonstrated that LSD1-kd abrogated Gfi1b-negative autoregulation by crossing LSD1-kd with Gfi1b:GFP mice. Taken together, our findings distinguish LSD1 as a critical regulator of hematopoiesis and point to severe, but reversible, side effects of a LSD1-targeted therapy.
Please use this url to cite or link to this publication:
author
organization
year
type
journalArticle (original)
publication status
published
subject
keyword
EPIGENETIC REGULATION, PROSTATE-CANCER, LSD1, ERYTHROID-DIFFERENTIATION, SELF-RENEWAL, ANDROGEN-RECEPTOR, STEM-CELLS, inhibited terminal differentiation, LSD1/KDM1A, progenitor expansion, hematopoiesis, ERYTHROPOIESIS, EXPRESSION, GENE
journal title
LEUKEMIA
Leukemia
volume
26
issue
9
pages
2039 - 2051
Web of Science type
Article
Web of Science id
000308342900009
JCR category
HEMATOLOGY
JCR impact factor
10.164 (2012)
JCR rank
2/66 (2012)
JCR quartile
1 (2012)
ISSN
0887-6924
DOI
10.1038/leu.2012.157
language
English
UGent publication?
yes
classification
A1
copyright statement
I have transferred the copyright for this publication to the publisher
id
3049107
handle
http://hdl.handle.net/1854/LU-3049107
date created
2012-11-08 12:02:33
date last changed
2012-11-08 12:08:29
@article{3049107,
  abstract     = {Lysine (K)-specific demethylase 1A (LSD1/KDM1A) has been identified as a potential therapeutic target in solid cancers and more recently in acute myeloid leukemia. However, the potential side effects of a LSD1-inhibitory therapy remain elusive. Here, we show, with a newly established conditional in vivo knockdown model, that LSD1 represents a central regulator of hematopoietic stem and progenitor cells. LSD1 knockdown (LSD1-kd) expanded progenitor numbers by enhancing their proliferative behavior. LSD1-kd led to an extensive expansion of granulomonocytic, erythroid and megakaryocytic progenitors. In contrast, terminal granulopoiesis, erythropoiesis and platelet production were severely inhibited. The only exception was monopoiesis, which was promoted by LSD1 deficiency. Importantly, we showed that peripheral blood granulocytopenia, monocytosis, anemia and thrombocytopenia were reversible after LSD1-kd termination. Extramedullary splenic hematopoiesis contributed to the phenotypic reversion, and progenitor populations remained expanded. LSD1-kd was associated with the upregulation of key hematopoietic genes, including Gfi1b, Hoxa9 and Meis1, which are known regulators of the HSC/progenitor compartment. We also demonstrated that LSD1-kd abrogated Gfi1b-negative autoregulation by crossing LSD1-kd with Gfi1b:GFP mice. Taken together, our findings distinguish LSD1 as a critical regulator of hematopoiesis and point to severe, but reversible, side effects of a LSD1-targeted therapy.},
  author       = {Spr{\"u}ssel, A and Schulte, JH and Weber, S and Necke, M and H{\"a}ndschke, K and Thor, T and Pajtler, KW and Schramm, A and K{\"o}nig, K and Diehl, L and Mestdagh, Pieter and Vandesompele, Jo and Speleman, Franki and Jastrow, H and Heukamp, LC and Sch{\"u}le, R and D{\"u}hrsen, U and Buettner, R and Eggert, A and G{\"o}thert, JR},
  issn         = {0887-6924},
  journal      = {LEUKEMIA},
  keyword      = {EPIGENETIC REGULATION,PROSTATE-CANCER,LSD1,ERYTHROID-DIFFERENTIATION,SELF-RENEWAL,ANDROGEN-RECEPTOR,STEM-CELLS,inhibited terminal differentiation,LSD1/KDM1A,progenitor expansion,hematopoiesis,ERYTHROPOIESIS,EXPRESSION,GENE},
  language     = {eng},
  number       = {9},
  pages        = {2039--2051},
  title        = {Lysine-specific demethylase 1 restricts hematopoietic progenitor proliferation and is essential for terminal differentiation},
  url          = {http://dx.doi.org/10.1038/leu.2012.157},
  volume       = {26},
  year         = {2012},
}

Chicago
Sprüssel, A, JH Schulte, S Weber, M Necke, K Händschke, T Thor, KW Pajtler, et al. 2012. “Lysine-specific Demethylase 1 Restricts Hematopoietic Progenitor Proliferation and Is Essential for Terminal Differentiation.” Leukemia 26 (9): 2039–2051.
APA
Sprüssel, A., Schulte, J., Weber, S., Necke, M., Händschke, K., Thor, T., Pajtler, K., et al. (2012). Lysine-specific demethylase 1 restricts hematopoietic progenitor proliferation and is essential for terminal differentiation. LEUKEMIA, 26(9), 2039–2051.
Vancouver
1.
Sprüssel A, Schulte J, Weber S, Necke M, Händschke K, Thor T, et al. Lysine-specific demethylase 1 restricts hematopoietic progenitor proliferation and is essential for terminal differentiation. LEUKEMIA. 2012;26(9):2039–51.
MLA
Sprüssel, A, JH Schulte, S Weber, et al. “Lysine-specific Demethylase 1 Restricts Hematopoietic Progenitor Proliferation and Is Essential for Terminal Differentiation.” LEUKEMIA 26.9 (2012): 2039–2051. Print.