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Molecular Targets for Therapy

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.

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Acknowledgements

We thank Tarik Möröy for the permission to use Gfi1b:GFP mice, Doris Schünke for excellent technical assistance performing electron microscopy, the WTZ hemato-oncology laboratory for technical support staining blood smears and cytospin preparations, and the WTZ Research Support Service (supported in part by the Deutsche Krebshilfe Comprehensive Cancer Center financing) for editing the manuscript. This work was supported by a grant to JHS from the Deutsche Krebshilfe (Nr. 108941), and grant support from the Stem Cell Network North-Rhine Westphalia to JRG.

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Correspondence to J R Göthert.

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Sprüssel, A., Schulte, J., Weber, S. et al. Lysine-specific demethylase 1 restricts hematopoietic progenitor proliferation and is essential for terminal differentiation. Leukemia 26, 2039–2051 (2012). https://doi.org/10.1038/leu.2012.157

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