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

(2012) LEUKEMIA. 26(9). p.2039-2051
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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
EPIGENETIC REGULATION, PROSTATE-CANCER, LSD1, ERYTHROID-DIFFERENTIATION, SELF-RENEWAL, ANDROGEN-RECEPTOR, STEM-CELLS, inhibited terminal differentiation, LSD1/KDM1A, progenitor expansion, hematopoiesis, ERYTHROPOIESIS, EXPRESSION, GENE

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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.
@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},
}

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