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

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Lysine-specific demethylase 1 restricts hematopoietic progenitor proliferation and is essential for terminal differentiation. / Sprüssel, A; Schulte, J H; Weber, S; Necke, M; Händschke, K; Thor, T; Pajtler, K W; Schramm, A; König, K; Diehl, L; Mestdagh, P; Vandesompele, J; Speleman, F; Jastrow, H; Heukamp, L C; Schüle, R; Dührsen, U; Buettner, R; Eggert, A; Göthert, J R.

In: LEUKEMIA, Vol. 26, No. 9, 09.2012, p. 2039-51.

Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review

Harvard

Sprüssel, A, Schulte, JH, Weber, S, Necke, M, Händschke, K, Thor, T, Pajtler, KW, Schramm, A, König, K, Diehl, L, Mestdagh, P, Vandesompele, J, Speleman, F, Jastrow, H, Heukamp, LC, Schüle, R, Dührsen, U, Buettner, R, Eggert, A & Göthert, JR 2012, 'Lysine-specific demethylase 1 restricts hematopoietic progenitor proliferation and is essential for terminal differentiation', LEUKEMIA, vol. 26, no. 9, pp. 2039-51. https://doi.org/10.1038/leu.2012.157

APA

Sprüssel, A., Schulte, J. H., Weber, S., Necke, M., Händschke, K., Thor, T., Pajtler, K. W., Schramm, A., König, K., Diehl, L., Mestdagh, P., Vandesompele, J., Speleman, F., Jastrow, H., Heukamp, L. C., Schüle, R., Dührsen, U., Buettner, R., Eggert, A., & Göthert, J. R. (2012). Lysine-specific demethylase 1 restricts hematopoietic progenitor proliferation and is essential for terminal differentiation. LEUKEMIA, 26(9), 2039-51. https://doi.org/10.1038/leu.2012.157

Vancouver

Sprüssel A, Schulte JH, 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 Sep;26(9):2039-51. https://doi.org/10.1038/leu.2012.157

Bibtex

@article{8abe944dbd2447ec824d40e7601ce5e1,
title = "Lysine-specific demethylase 1 restricts hematopoietic progenitor proliferation and is essential for terminal differentiation",
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.",
keywords = "Animals, Blotting, Western, Cell Differentiation, Cell Proliferation, Erythropoiesis, Female, Flow Cytometry, Granulocytes, Hematopoiesis, Histone Demethylases, Humans, Integrases, Male, Megakaryocytes, Mice, Mice, Transgenic, Oxidoreductases, N-Demethylating, Proto-Oncogene Proteins, Repressor Proteins, Stem Cells",
author = "A Spr{\"u}ssel and Schulte, {J H} and S Weber and M Necke and K H{\"a}ndschke and T Thor and Pajtler, {K W} and A Schramm and K K{\"o}nig and L Diehl and P Mestdagh and J Vandesompele and F Speleman and H Jastrow and Heukamp, {L C} and R Sch{\"u}le and U D{\"u}hrsen and R Buettner and A Eggert and G{\"o}thert, {J R}",
year = "2012",
month = sep,
doi = "10.1038/leu.2012.157",
language = "English",
volume = "26",
pages = "2039--51",
journal = "LEUKEMIA",
issn = "0887-6924",
publisher = "NATURE PUBLISHING GROUP",
number = "9",

}

RIS

TY - JOUR

T1 - Lysine-specific demethylase 1 restricts hematopoietic progenitor proliferation and is essential for terminal differentiation

AU - Sprüssel, A

AU - Schulte, J H

AU - Weber, S

AU - Necke, M

AU - Händschke, K

AU - Thor, T

AU - Pajtler, K W

AU - Schramm, A

AU - König, K

AU - Diehl, L

AU - Mestdagh, P

AU - Vandesompele, J

AU - Speleman, F

AU - Jastrow, H

AU - Heukamp, L C

AU - Schüle, R

AU - Dührsen, U

AU - Buettner, R

AU - Eggert, A

AU - Göthert, J R

PY - 2012/9

Y1 - 2012/9

N2 - 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.

AB - 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.

KW - Animals

KW - Blotting, Western

KW - Cell Differentiation

KW - Cell Proliferation

KW - Erythropoiesis

KW - Female

KW - Flow Cytometry

KW - Granulocytes

KW - Hematopoiesis

KW - Histone Demethylases

KW - Humans

KW - Integrases

KW - Male

KW - Megakaryocytes

KW - Mice

KW - Mice, Transgenic

KW - Oxidoreductases, N-Demethylating

KW - Proto-Oncogene Proteins

KW - Repressor Proteins

KW - Stem Cells

U2 - 10.1038/leu.2012.157

DO - 10.1038/leu.2012.157

M3 - SCORING: Journal article

C2 - 22699452

VL - 26

SP - 2039

EP - 2051

JO - LEUKEMIA

JF - LEUKEMIA

SN - 0887-6924

IS - 9

ER -