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GEO help: Mouse over screen elements for information. |
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| Status |
Public on Sep 26, 2013 |
| Title |
Gene expression changes associated with progression of Irf8–/– CML-like disease into blast crisis after β-catenin activation |
| Organism |
Mus musculus |
| Experiment type |
Expression profiling by array
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| Summary |
Progression and disease relapse of chronic myeloid leukemia (CML) depends on leukemia-initiating cells (LIC) that resist treatment. Using mouse genetics, we observed that compound constitutive activation of β-catenin and deletion of Irf8 results in progression of CML-like disease into fatal blast crisis, elevated leukemic potential of BCR-ABL-induced LICs, and accumulation of Imatinib-resistant LICs in GMP-like populations. We found that progression of the disease is tightly connected to the magnitude of gene expression and that activated β-catenin enhances a pre-existing Irf8-deficient gene signature that was defined as a “progression specific signature” (PSS). We identified β-catenin as an amplifier of disease progression and as a critical step in the shift of CML to blast crisis. Collectively, our data uncover Irf8 as a roadblock for β-catenin-driven leukemia and imply both factors as targets in combinatorial therapy.
We used microarrays to identify the gene expression signature in GMPs underlying CML-like disease progression and identified distinct classes of up- and down-regulated genes during this process defined as a “progression specific signature (PSS)”.
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| Overall design |
GMP populations were sorted from three to four independent pools of control MxCre–Ctnnb1(Ex3)fl/+, Ctnnb1(Ex3)∆/+, Irf8–/–Ctnnb1(Ex3)fl/+ and Irf8–/–Ctnnb1(Ex3)∆/+ mice for RNA extraction and hybridization on Affymetrix Mouse 430_2 chip arrays (MG-430 PM peg arrays; Affymetrix GeneChip). Cells were sorted using FACSAria (BD Biosciences Immunocytometry Systems, San Jose, CA) flow cytometers and GMPs defined as lineage depleted Lin– Sca-1–c-Kit+CD34+FcR II/IIIhi population. All mice were treated with 400µg polyinosinic-polycytidylic acid (poly(I:C)) (Amersham) on day 0, 3 and 5 to induce β-catenin activation (MxCre-dependent excision of Exon3 in the β-catenin gene). Harvesting of bone marrow cells were performed 10-14 days after the last poly(I:C) injection. We used heterozygous inducible MxCre+Ctnnb1(Ex3)fl/+ mice because of the dominant effect from a single activated Ctnnb1 allele. To validate excision efficiency, genomic DNA from harvested cells was subjected to PCR, as previously described (Huelsken et al., 2001; Scheller et al., 2006).
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| Contributor(s) |
Scheller M, Schönheit J, Zimmermann K, Leser U, Rosenbauer F, Leutz A |
| Citation(s) |
24101380 |
| Submission date |
Jul 19, 2013 |
| Last update date |
Aug 06, 2018 |
| Contact name |
Marina Scheller |
| E-mail(s) |
marina.scheller@gmx.net
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| Organization name |
MDC Berlin
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| Street address |
Robert-Rössle-Str. 10
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| City |
Berlin |
| ZIP/Postal code |
13125 |
| Country |
Germany |
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| Platforms (1) |
| GPL11180 |
[HT_MG-430_PM] Affymetrix HT MG-430 PM Array Plate |
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| Samples (11)
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| Relations |
| BioProject |
PRJNA213468 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE49054_PSS_progression_specific_signature.txt.gz |
33.0 Kb |
(ftp)(http) |
TXT |
| GSE49054_RAW.tar |
22.0 Mb |
(http)(custom) |
TAR (of CEL) |
| Processed data included within Sample table |
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