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| Status |
Public on Apr 09, 2009 |
| Title |
Linkage of Meis1 leukemogenic activity to multiple downstream effectors including Trib2 and Ccl3 |
| Organism |
Mus musculus |
| Experiment type |
Expression profiling by array
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| Summary |
OBJECTIVE: MEIS1, a HOX cofactor, collaborates with multiple HOX and NUP98-HOX fusion proteins to accelerate the onset of acute myeloid leukemia (AML) through largely unknown molecular mechanisms. MATERIALS AND METHODS: To further resolve these mechanisms, we conducted a structure-function analysis of MEIS1 and gene-expression profiling, in the context of NUP98-HOXD13 (ND13) leukemogenesis. RESULTS: We show, in a murine bone marrow transplantation model, that the PBX-interaction domain, the homeodomain, and the C-terminal domain of MEIS1, are all required for leukemogenic collaboration with ND13. In contrast, the N-terminal domain of MEIS1 is dispensable for collaboration with ND13, but is required for Flt3 upregulation, indicating additional roles for MEIS1 in induction of leukemia independent of alterations in Flt3 expression. Gene-expression profiling of a cloned ND13 preleukemic cell line transduced with wild-type or Meis1 mutant forms revealed deregulation of multiple genes, including a set not previously implicated as MEIS1 targets. Chromatin immunoprecipitation revealed the in vivo occupancy of MEIS1 on regulatory sequences of Trib2, Flt3, Dlk1, Ccl3, Ccl4, Pf4, and Rgs1. Furthermore, engineered overexpression of Trib2 complements ND13 to induce AML while Ccl3 potentiates the repopulating ability of ND13. CONCLUSION: This study shows that Meis1-induced leukemogenesis with ND13 can occur in the absence of Flt3 upregulation and reveals the existence of other pathways activated by MEIS1 to promote leukemia.
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| Overall design |
Establishment of pre-leukemic bone marrow cell lines following transduction with ND13 have been previously described (Pineault, Abramovich et al. 2005). In brief, lines were established from BM cells previously treated with 5-fluorouracil (5-FU) from (C57Bl/6Ly-Pep3b x C3H/HeJ) F1 (PepC3) (Ly5.1+/Ly5.2+) mice freshly transduced with the ND13-GFP or ND13pac virus and maintained in liquid culture. To generate ND13+Meis1 or ND13+Meis1 mutant BM cell lines, the ND13 BM cells were transduced by co-cultivation on irradiated (4,000 cGy) E86 producers for Meis1-YFP (or Meis1 mutant forms), respectively, for a period of 2 days in the presence of 5 µg/ml of protamine sulfate. Three independent experiments were performed for each of the four different conditions included in the study.
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| Contributor(s) |
Argiropoulos B, Palmqvist L, Yung E, Kuchenbauer F, Heuser M, Sly LM, Wan A, Krystal G, Humphries KR |
| Citation(s) |
18375036 |
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| Submission date |
Apr 03, 2009 |
| Last update date |
Feb 11, 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) |
| GPL1261 |
[Mouse430_2] Affymetrix Mouse Genome 430 2.0 Array |
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| Samples (12)
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| Relations |
| BioProject |
PRJNA115973 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE15541_RAW.tar |
45.0 Mb |
(http)(custom) |
TAR (of CEL, CHP) |
| Processed data included within Sample table |
| Processed data provided as supplementary file |
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