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| Status |
Public on May 01, 2014 |
| Title |
Expression analysis of common myeloid progenitors (CMPs) expressing Hes1 |
| Organism |
Mus musculus |
| Experiment type |
Expression profiling by array
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| Summary |
High levels of Hes1 expression are frequently found in BCR-ABL-positive chronic myelogenous leukemia in blast crisis (CML-BC). In mouse bone marrow transplantation (BMT) models, co-expression of BCR-ABL and Hes1 induces CML-BC–like disease; however the underlying mechanism remained elusive. Here, based on gene expression analysis, we show that MMP-9 is upregulated by Hes1 in common myeloid progenitors (CMPs). Analysis of promoter activity demonstrated that Hes1 upregulated MMP-9 by activating NF-kB. Analysis of 20 samples from CML-BC patients showed that MMP-9 was highly expressed in three, with two exhibiting high levels of Hes1 expression. Interestingly, MMP-9 deficiency impaired the cobblestone area-forming ability of CMPs expressing BCR-ABL and Hes1 that were in conjunction with a stromal cell layer. In addition, these CMPs secreted MMP-9, promoting the release of soluble Kit-ligand (sKitL) from stromal cells, thereby enhancing proliferation of the leukemic cells. In accordance, mice transplanted with CMPs expressing BCR-ABL and Hes1 exhibited high levels of sKitL as well as MMP-9 in the serum. Importantly, MMP-9 deficiency impaired the development of CML-BC–like disease induced by BCR-ABL and Hes1 in mouse BMT models. The present results suggest that Hes1 promotes the development of CML-BC, partly through MMP-9 upregulation in leukemic cells.
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| Overall design |
Common myeloid progenitors (CMPs; Lineage negative, c-Kit positive, Sca-1 negative, Fc-gamma-receptor low, CD34 positive fraction) were sorted with a FACSAria cell sorter (Becton Dickinson). Retroviruses were generated by transfecting Plat-E packaging cells with retrovirus vector pMYs-Hes1-IRES-GFP or empty vector (pMYs-IRES-GFP) using FuGENE 6 (Roche Diagnostics). Infection of retrovirus harboring Hes1 (pMYs-Hes1-IRES-GFP) or empty vector (pMYs-IRES-GFP) into progenitors was performed using RetroNectin (Takara Bio). Hes1-transfected CMPs and Mock-transduced CMPs were isolated 36 hours after infection with a FACSAria cell sorter. One sample of Hes1-transfected CMPs and one sample of mock-transduced CMPs were analyzed with GeneChip Mouse Genome 430 2.0 Array.
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| Contributor(s) |
Nakahara F, Aburatani H, Kitamura T |
| Citation(s) |
24825862 |
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| Submission date |
Apr 18, 2014 |
| Last update date |
Feb 11, 2019 |
| Contact name |
Fumio Nakahara |
| Organization name |
The Institute of Medical Science, The University of Tokyo
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| Department |
Division of Cellular Therapy, Advanced Clinical Research Center
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| Street address |
4-6-1 Shirokanedai, Minato-ku
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| City |
Tokyo |
| ZIP/Postal code |
108-8639 |
| Country |
Japan |
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| Platforms (1) |
| GPL1261 |
[Mouse430_2] Affymetrix Mouse Genome 430 2.0 Array |
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| Samples (2) |
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| Relations |
| BioProject |
PRJNA244936 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE56921_RAW.tar |
11.7 Mb |
(http)(custom) |
TAR (of CEL) |
| Processed data included within Sample table |
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