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.