Submitted on September 29, 2005
Accepted on February 13, 2007
Gene-Expression Analysis of Hematopoietic Progenitor Cells Identifies Dlg7 as a Potential Stem-Cell Gene
Kristbjorn Orri Gudmundsson 1*,
Leifur Thorsteinsson 1,
Olafur E. Sigurjonsson 2,
Jonathan R. Keller 3,
Karl Olafsson 4,
Torstein Egeland 5,
Sveinn Gudmundsson 1,
Thorunn Rafnar 6
1 The Blood Bank, Landspitali - University Hospital, Reykjavík, Iceland
2 The Blood Bank, Landspitali - University Hospital, Reykjavík, Iceland; Institute of Immunology, University Hospital, Oslo, Norway
3 Basic Research Program, SAIC-Frederick, Inc., Center for Cancer Research, National Cancer Institute, Frederick, Maryland
4 Department of Obstetrics and Gynecology, Landspitali - University Hospital, Reykjavík, Iceland
5 Institute of Immunology, University Hospital, Oslo, Norway
6 Iceland Genomics Corporation, Reykjavík, Iceland
* To whom correspondence should be addressed. E-mail: kristbj{at}landspitali.is.
 |
Abstract |
|---|
Inducible hematopoietic stem/progenitor cell lines represent a model for studying genes involved in self-renewal and differentiation. Here, gene expression was studied in the inducible human CD34+ acute myelogenous leukemia cell line KG1 using oligonucleotide arrays and suppression subtractive cloning. Using this approach, we identified Dlg7, the homologue of the Drosophila Dlg1 tumor suppressor gene, as downregulated at the early stages of KG1 differentiation. Similarly, Dlg7 was expressed in normal purified umbilical cord blood CD34+CD38- progenitors but not in the more committed CD34+CD38+ population. Dlg7 expression was not detected in differentiated cells obtained from hematopoietic colonies nor was expression detected in purified T-cells, B-cells and monocytes. When analyzed in different types of stem cells, Dlg7 expression was detected in purified human bone marrow derived CD133+ progenitor cells, human mesenchymal stem cells and mouse embryonic stem (ES) cells. Overexpression of Dlg7 in mouse ES cells increased their growth rate and reduced the number of embryoid bodies (EBs) emerging upon differentiation. In addition, the EBs were significantly smaller indicating an inhibition in differentiation. This inhibition was further supported by higher expression of Bmp4, Oct4, Rex1 and Nanog in EBs overexpressing Dlg7 and lower expression of Brachyury. Finally, the Dlg7 protein was detected in liver and coIon carcinoma tumors but not in normal adjacent tissues suggesting a role for the gene in carcinogenesis. In conclusion, our results suggest that Dlg7 has a role in stem cell survival, in maintaining stem cell properties and in carcinogenesis.
Key Words.
Human, Hematopoietic Progenitor Cells, Embryonic Stem Cells, Gene Expression
