Open AccessReduced Erg Dosage Impairs Survival of Hematopoietic Stem and Progenitor Cells
Author(s) -
Xie Ying,
Koch Mia Lee,
Zhang Xin,
Hamblen Melanie J.,
Godinho Frank J.,
Fujiwara Yuko,
Xie Huafeng,
Klusmann JanHenning,
Orkin Stuart H.,
Li Zhe
Publication year - 2017
Publication title -
stem cells
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.159
H-Index - 229
eISSN - 1549-4918
pISSN - 1066-5099
DOI - 10.1002/stem.2627
Subject(s) - biology , haematopoiesis , progenitor cell , stem cell , microbiology and biotechnology , cre recombinase , bone marrow , erg , cancer research , endothelial stem cell , immunology , genetics , transgene , in vitro , gene , genetically modified mouse , retina , neuroscience
ERG, an ETS family transcription factor frequently overexpressed in human leukemia, has been implicated as a key regulator of hematopoietic stem cells. However, how ERG controls normal hematopoiesis, particularly at the stem and progenitor cell level, and how it contributes to leukemogenesis remain incompletely understood. Using homologous recombination, we generated an Erg knockdown allele ( Erg kd ) in which Erg expression can be conditionally restored by Cre recombinase. Erg kd/kd animals die at E10.5–E11.5 due to defects in endothelial and hematopoietic cells, but can be completely rescued by Tie2‐Cre ‐mediated restoration of Erg in these cells. In Erg kd/+ mice, ∼40% reduction in Erg dosage perturbs both fetal liver and bone marrow hematopoiesis by reducing the numbers of Lin – Sca‐1 + c‐Kit + (LSK) hematopoietic stem and progenitor cells (HSPCs) and megakaryocytic progenitors. By genetic mosaic analysis, we find that Erg ‐restored HSPCs outcompete Erg kd/+ HSPCs for contribution to adult hematopoiesis in vivo. This defect is in part due to increased apoptosis of HSPCs with reduced Erg dosage, a phenotype that becomes more drastic during 5‐FU‐induced stress hematopoiesis. Expression analysis reveals that reduced Erg expression leads to changes in expression of a subset of ERG target genes involved in regulating survival of HSPCs, including increased expression of a pro‐apoptotic regulator Bcl2l11 ( Bim ) and reduced expression of Jun . Collectively, our data demonstrate that ERG controls survival of HSPCs, a property that may be used by leukemic cells. S tem C ells 2017;35:1773–1785