Go to JCI Insight
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Publication alerts by email
  • Advertising
  • Job board
  • Contact
  • Clinical Research and Public Health
  • Current issue
  • Past issues
  • By specialty
    • COVID-19
    • Cardiology
    • Gastroenterology
    • Immunology
    • Metabolism
    • Nephrology
    • Neuroscience
    • Oncology
    • Pulmonology
    • Vascular biology
    • All ...
  • Videos
    • Conversations with Giants in Medicine
    • Video Abstracts
  • Reviews
    • View all reviews ...
    • Complement Biology and Therapeutics (May 2025)
    • Evolving insights into MASLD and MASH pathogenesis and treatment (Apr 2025)
    • Microbiome in Health and Disease (Feb 2025)
    • Substance Use Disorders (Oct 2024)
    • Clonal Hematopoiesis (Oct 2024)
    • Sex Differences in Medicine (Sep 2024)
    • Vascular Malformations (Apr 2024)
    • View all review series ...
  • Viewpoint
  • Collections
    • In-Press Preview
    • Clinical Research and Public Health
    • Research Letters
    • Letters to the Editor
    • Editorials
    • Commentaries
    • Editor's notes
    • Reviews
    • Viewpoints
    • 100th anniversary
    • Top read articles

  • Current issue
  • Past issues
  • Specialties
  • Reviews
  • Review series
  • Conversations with Giants in Medicine
  • Video Abstracts
  • In-Press Preview
  • Clinical Research and Public Health
  • Research Letters
  • Letters to the Editor
  • Editorials
  • Commentaries
  • Editor's notes
  • Reviews
  • Viewpoints
  • 100th anniversary
  • Top read articles
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Publication alerts by email
  • Advertising
  • Job board
  • Contact
Cis-element mutated in GATA2-dependent immunodeficiency governs hematopoiesis and vascular integrity
Kirby D. Johnson, … , Steven M. Holland, Emery H. Bresnick
Kirby D. Johnson, … , Steven M. Holland, Emery H. Bresnick
Published September 10, 2012
Citation Information: J Clin Invest. 2012;122(10):3692-3704. https://doi.org/10.1172/JCI61623.
View: Text | PDF
Research Article Article has an altmetric score of 25

Cis-element mutated in GATA2-dependent immunodeficiency governs hematopoiesis and vascular integrity

  • Text
  • PDF
Abstract

Haploinsufficiency for GATA2 causes human immunodeficiency syndromes characterized by mycobacterial infection, myelodysplasia, lymphedema, or aplastic anemia that progress to myeloid leukemia. GATA2 encodes a master regulator of hematopoiesis that is also linked to endothelial biology. Though the disease-causing mutations commonly occur in the GATA-2 DNA binding domain, we identified a patient with mycobacterial infection and myelodysplasia who had an uncharacterized heterozygous deletion in a GATA2cis-element consisting of an E-box and a GATA motif. Targeted deletion of the equivalent murine element to yield homozygous mutant mice revealed embryonic lethality later than occurred with global Gata2 knockout, hematopoietic stem/progenitor cell depletion, and impaired vascular integrity. Heterozygous mutant mice were viable, but embryos exhibited deficits in definitive, but not primitive, hematopoietic stem/progenitor activity and reduced expression of Gata2 and its target genes. Mechanistic analysis revealed disruption of the endothelial cell transcriptome and loss of vascular integrity. Thus, the composite element disrupted in a human immunodeficiency is essential for establishment of the murine hematopoietic stem/progenitor cell compartment in the fetal liver and for essential vascular processes.

Authors

Kirby D. Johnson, Amy P. Hsu, Myung-Jeom Ryu, Jinyong Wang, Xin Gao, Meghan E. Boyer, Yangang Liu, Youngsook Lee, Katherine R. Calvo, Sunduz Keles, Jing Zhang, Steven M. Holland, Emery H. Bresnick

×

Figure 6

Severe depletion of functional hematopoietic stem cells in +9.5–/– embryos.

Options: View larger image (or click on image) Download as PowerPoint
Severe depletion of functional hematopoietic stem cells in +9.5–/– embry...
E12.5 fetal liver cells (CD45.2) from +9.5+/+, +9.5+/–, and +9.5–/– littermates were transplanted into irradiated CD45.1 recipient mice at a 1:1 ratio with CD45.2+ bone marrow cells. Peripheral blood was analyzed by flow cytometry 6 and 10 weeks after transplantation. (A) CD45.2+ cells in recipient mice expressed as percentage of total live nucleated cells. Data are presented as mean ± SEM. The contribution from +9.5+/– and +9.5–/– donors was significantly reduced compared with +9.5+/+ littermates as indicated (*P < 0.05). (B) The contribution of +9.5+/+ and +9.5+/– donor-derived CD45.2 cells to peripheral blood monocytes (Mac1+Gr-1–), granulocytes (Mac1+Gr-1+), T cells (Thy1.2+), and B cells (CD19+). At 10 weeks, significant increases in CD45.2+ T cells (P = 0.042) and B cells (P = 0.012) were observed in recipients of fetal liver cell transplants from +9.5+/– donors compared with +9.5+/+ littermate controls. Similar results were obtained in an additional transplantation experiment using 150,000 live nucleated fetal liver cells and 300,000 bone marrow cells (data not shown)

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

Sign up for email alerts

Picked up by 2 news outlets
Posted by 2 X users
Referenced in 4 patents
On 1 Facebook pages
101 readers on Mendeley
See more details