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- aggregation classification "A1".
- aggregation creator B583573.
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- aggregation creator person.
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- aggregation date "2012".
- aggregation format "application/pdf".
- aggregation hasFormat 3049107.bibtex.
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- aggregation isPartOf urn:issn:0887-6924.
- aggregation language "eng".
- aggregation rights "I have transferred the copyright for this publication to the publisher".
- aggregation subject "Biology and Life Sciences".
- aggregation title "Lysine-specific demethylase 1 restricts hematopoietic progenitor proliferation and is essential for terminal differentiation".
- aggregation 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.".
- aggregation authorList BK936243.
- aggregation endPage "2051".
- aggregation issue "9".
- aggregation startPage "2039".
- aggregation volume "26".
- aggregation aggregates 3049135.
- aggregation isDescribedBy 3049107.
- aggregation similarTo leu.2012.157.
- aggregation similarTo LU-3049107.