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| Status |
Public on Oct 01, 2007 |
| Title |
Candidate Genes for Expansion and Transformation of Hematopoietic Stem Cells by NUP98-HOX Fusion Genes |
| Organism |
Mus musculus |
| Experiment type |
Expression profiling by array
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| Summary |
BACKGROUND: Hox genes are implicated in hematopoietic stem cell (HSC) regulation as well as in leukemia development through translocation with the nucleoporin gene NUP98. Interestingly, an engineered NUP98-HOXA10 (NA10) fusion can induce a several hundred-fold expansion of HSCs in vitro and NA10 and the AML-associated fusion gene NUP98-HOXD13 (ND13) have a virtually indistinguishable ability to transform myeloid progenitor cells in vitro and to induce leukemia in collaboration with MEIS1 in vivo. METHODOLOGY/PRINCIPAL FINDINGS: These findings provided a potentially powerful approach to identify key pathways mediating Hox-induced expansion and transformation of HSCs by identifying gene expression changes commonly induced by ND13 and NA10 but not by a NUP98-Hox fusion with a non-DNA binding homedomain mutation (N51S). The gene expression repertoire of purified murine bone marrow Sca-1+Lin- cells transduced with retroviral vectors encoding for these genes was established using the Affymetrix GeneChip MOE430A. Approximately seventy genes were differentially expressed in ND13 and NA10 cells that were significantly changed by both compared to the ND13(N51S) mutant. Intriguingly, several of these potential Hox target genes have been implicated in HSC expansion and self-renewal, including the tyrosine kinase receptor Flt3, the prion protein, Prnp, hepatic leukemia factor, Hlf and Jagged-2, Jag2. CONCLUSIONS: In conclusion this study has identified several novel Hox downstream target genes and provides important new leads to key regulators of the expansion and transformation of hematopoietic stem cells by Hox.
Keywords: Leukemic vs. non-leukemic NUP98-HOX fusion genes
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| Overall design |
Adult murine bone marrow cells transduced with vectors carrying ND13, NA10, ND13(N51S) or an empty GFP control vector (MIG) were isolated on the basis of GFP expression by FACS 24 hours post-transduction. Viable transduced cells were further enriched for primitive hematopoietic cells by exclusion of cells expressing linage markers (Gr-1, B220, Ter-119, CD4, CD5 and CD8) and selection for cells expressing the stem cell antigen-1 (Sca-1). Three independent experiments were performed for each of the four different conditions included in the study.
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| Contributor(s) |
Palmqvist L, Humphries KR |
| Citation(s) |
17712416 |
| Submission date |
Sep 18, 2007 |
| Last update date |
Jan 08, 2019 |
| Contact name |
Lars Palmqvist |
| E-mail(s) |
lars.palmqvist@clinchem.gu.se
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| Organization name |
University of Gothenburg
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| Department |
Institute of Biomedicine
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| Lab |
Department of Laboratory Medicine
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| Street address |
Sahlgrenska University Hospital
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| City |
Gothenburg |
| ZIP/Postal code |
41345 |
| Country |
Sweden |
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| Platforms (1) |
| GPL339 |
[MOE430A] Affymetrix Mouse Expression 430A Array |
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| Samples (12)
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| Relations |
| BioProject |
PRJNA102599 |
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