دورية أكاديمية
أعرض في EDS

Reduced Erg Dosage Impairs Survival of Hematopoietic Stem and Progenitor Cells.

التفاصيل البيبلوغرافية
العنوان: Reduced Erg Dosage Impairs Survival of Hematopoietic Stem and Progenitor Cells.
المؤلفون: Xie Y; Division of Genetics, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA.; Department of Medicine, Boston, Massachusetts, USA., Koch ML; Division of Genetics, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA.; Department of Pediatric Hematology and Oncology, Hannover Medical School, Hannover, Germany., Zhang X; Division of Genetics, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA., Hamblen MJ; Division of Hematology and Oncology, Boston Children's Hospital, Boston, Massachusetts, USA.; Howard Hughes Medical Institute, Boston, Massachusetts, USA., Godinho FJ; Division of Hematology and Oncology, Boston Children's Hospital, Boston, Massachusetts, USA.; Howard Hughes Medical Institute, Boston, Massachusetts, USA., Fujiwara Y; Division of Hematology and Oncology, Boston Children's Hospital, Boston, Massachusetts, USA.; Howard Hughes Medical Institute, Boston, Massachusetts, USA.; Department of Pediatrics, Harvard Medical School, Boston, Massachusetts, USA., Xie H; Division of Hematology and Oncology, Boston Children's Hospital, Boston, Massachusetts, USA.; Department of Pediatrics, Harvard Medical School, Boston, Massachusetts, USA.; Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA., Klusmann JH; Department of Pediatric Hematology and Oncology, Hannover Medical School, Hannover, Germany., Orkin SH; Division of Hematology and Oncology, Boston Children's Hospital, Boston, Massachusetts, USA.; Howard Hughes Medical Institute, Boston, Massachusetts, USA.; Department of Pediatrics, Harvard Medical School, Boston, Massachusetts, USA.; Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA., Li Z; Division of Genetics, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA.; Department of Medicine, Boston, Massachusetts, USA.
المصدر: Stem cells (Dayton, Ohio) [Stem Cells] 2017 Jul; Vol. 35 (7), pp. 1773-1785. Date of Electronic Publication: 2017 Apr 24.
نوع المنشور: Journal Article; Research Support, Non-U.S. Gov't; Research Support, N.I.H., Extramural
اللغة: English
بيانات الدورية: Publisher: Oxford University Press Country of Publication: England NLM ID: 9304532 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1549-4918 (Electronic) Linking ISSN: 10665099 NLM ISO Abbreviation: Stem Cells Subsets: MEDLINE
أسماء مطبوعة: Publication: 2022- : Oxford : Oxford University Press
Original Publication: Dayton, OH : AlphaMed Press, c1993-
مواضيع طبية MeSH: Gene Dosage*, Apoptosis/*genetics , Hematopoiesis/*genetics , Hematopoietic Stem Cells/*metabolism , Oncogene Proteins/*genetics , Transcriptional Regulator ERG/*genetics, Animals ; Antimetabolites/pharmacology ; Apoptosis/drug effects ; Bcl-2-Like Protein 11/genetics ; Bcl-2-Like Protein 11/metabolism ; Bone Marrow Cells/cytology ; Bone Marrow Cells/drug effects ; Bone Marrow Cells/metabolism ; Female ; Fluorouracil/pharmacology ; Gene Expression Profiling ; Gene Expression Regulation ; Genetic Complementation Test ; Hematopoiesis/drug effects ; Hematopoietic Stem Cells/cytology ; Hematopoietic Stem Cells/drug effects ; Integrases/genetics ; Integrases/metabolism ; Male ; Megakaryocytes/cytology ; Megakaryocytes/drug effects ; Megakaryocytes/metabolism ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Oncogene Proteins/deficiency ; Proto-Oncogene Proteins c-jun/genetics ; Proto-Oncogene Proteins c-jun/metabolism ; Signal Transduction ; Transcriptional Regulator ERG/deficiency
مستخلص: 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. Stem Cells 2017;35:1773-1785.
(© 2017 AlphaMed Press.)
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معلومات مُعتمدة: R01 HL107663 United States HL NHLBI NIH HHS; U54 DK110805 United States DK NIDDK NIH HHS
فهرسة مساهمة: Keywords: Animal models; Apoptosis; Hematopoietic progenitors; Hematopoietic stem cells; Leukemia; Transcription factors
المشرفين على المادة: 0 (Antimetabolites)
0 (Bcl-2-Like Protein 11)
0 (Bcl2l11 protein, mouse)
0 (ERG protein, mouse)
0 (Oncogene Proteins)
0 (Proto-Oncogene Proteins c-jun)
0 (Transcriptional Regulator ERG)
EC 2.7.7.- (Cre recombinase)
EC 2.7.7.- (Integrases)
U3P01618RT (Fluorouracil)
تواريخ الأحداث: Date Created: 20170425 Date Completed: 20180323 Latest Revision: 20181113
رمز التحديث: 20240829
مُعرف محوري في PubMed: PMC5532742
DOI: 10.1002/stem.2627
PMID: 28436588
قاعدة البيانات: MEDLINE
الوصف
تدمد:1549-4918
DOI:10.1002/stem.2627