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PMID: 20089964 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Knockdown of Fanconi anemia genes in human embryonic stem cells reveals early developmental defects in the hematopoietic lineage.

Blood ·Vol. 115 ·No. 17 ·2010-04-29 ·Pages 3453-62

Tulpule A, Lensch MW, Miller JD, Austin K, D'Andrea A, Schlaeger TM, Shimamura A, Daley GQ

Abstract

Fanconi anemia (FA) is a genetically heterogeneous, autosomal recessive disorder characterized by pediatric bone marrow failure and congenital anomalies. The effect of FA gene deficiency on hematopoietic development in utero remains poorly described as mouse models of FA do not develop hematopoietic failure and such studies cannot be performed on patients. We have created a human-specific in vitro system to study early hematopoietic development in FA using a lentiviral RNA interference (RNAi) strategy in human embryonic stem cells (hESCs). We show that knockdown of FANCA and FANCD2 in hESCs leads to a reduction in hematopoietic fates and progenitor numbers that can be rescued by FA gene complementation. Our data indicate that hematopoiesis is impaired in FA from the earliest stages of development, suggesting that deficiencies in embryonic hematopoiesis may underlie the progression to bone marrow failure in FA. This work illustrates how hESCs can provide unique insights into human development and further our understanding of genetic disease.

MeSH Terms
Bone Marrow/metabolism,pathology Cell Line Embryonic Stem Cells/metabolism,pathology Fanconi Anemia/genetics,metabolism,pathology Fanconi Anemia Complementation Group A Protein Fanconi Anemia Complementation Group D2 Protein Gene Knockdown Techniques Hematopoiesis/genetics Hematopoietic Stem Cells/metabolism,pathology Humans Models, Biological RNA Interference
Chemicals
FANCA protein, human FANCD2 protein, human Fanconi Anemia Complementation Group A Protein Fanconi Anemia Complementation Group D2 Protein
Authors & Affiliations
8 authors, click to expand affiliations / ORCID
Tulpule Asmin
Stem Cell Transplantation Program, Division of Pediatric Hematology/Oncology, Children's Hospital Boston and Dana-Farber Cancer Institute, MA, USA.
Lensch M William
Miller Justine D
Austin Karyn
D'Andrea Alan
Schlaeger Thorsten M
Shimamura Akiko
Daley George Q
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Article Info
Journal
Blood
Abbr.
Blood
ISSN
1528-0020
DOI
10.1182/blood-2009-10-246694
Published
2010-04-29
Epub
2010-00-20
Pages
3453-62
Language
English
Region
United States
NLM ID
7603509
PMCID
PMC2867260
Subset
IM
Grants
NIH HHS · DP1 OD000256 · United States
NHLBI NIH HHS · R01 HL079582 · United States
NHLBI NIH HHS · U01 HL100001 · United States
Howard Hughes Medical Institute · United States
Corrections
CommentIn
PMID: 20430961
External Links
PubMed source DOI: 10.1182/blood-2009-10-246694 PMC Full Text View journal details
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