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GEO help: Mouse over screen elements for information. |
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| Status |
Public on Feb 06, 2017 |
| Title |
Loss of Ikaros tumor suppressor function in a mouse model of BCR-ABL1-induced B-ALL correlates with a developmental block at a highly proliferative stage |
| Organism |
Mus musculus |
| Experiment type |
Expression profiling by high throughput sequencing
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| Summary |
Deletions within the human IKZF1 gene, which encodes Ikaros, a zinc finger transcription factor critical for lymphopoiesis, appear to be the most prominent recurring lesion in human BCR-ABL1+ (Ph+) B-ALL. Furthermore, IKZF1 mutations correlate with poor prognosis of progenitor B-ALL, further strengthening the notion that IKZF1 is a critical tumor suppressor gene in human B-lineage malignancies. To better understand the relationship between Ikzf1 mutations, BCR-ABL, and B-lineage leukemia, we examined the effect of two newly generated Ikzf1 germline mutation on BCR-ABL-induced proliferation and leukemogenesis in vitro and in vivo. We recently showed that deletion of either the exon encoding the first or the fourth DNA-binding zinc finger of Ikaros (IkZnF1-/- and IkZnF4-/-) led to distinct defects in lymphoid development and tumor suppression with de-regulation of distinct subsets of genes, providing a powerful tool for elucidation of Ikaros target genes and mechanism of function. Importantly, IkZnF4-/- had lost Ikaros tumor suppression function, while not abolishing B-cell development. Retroviral expression of BCR-ABL1 p185 in bone marrow cells from the two Ikzf1 mutant strains demonstrated that loss of ZnF4 resulted in expansion of progenitor B cells, with enhanced proliferation in vitro and a less mature cell surface B-cell phenotype in comparison to transduced wild-type bone marrow. Furthermore, in an in vivo model of BCR-ABL+ B-ALL, leukemias generated in the IkZnF4-/- background were more aggressive than those observed in a wild-type background, with cell phenotype corresponding to the in vitro cell cultures. Genome wide high throughput expression analysis (RNA-Seq) revealed a distinct subset of deregulated genes in the IkZnF4-/- BCR-ABL+ in vitro cell cultures, and molecular analysis demonstrated that this in vitro system is amendable for functional studies. These results establish a mouse model for studying the role of Ikzf1 mutations in B-ALL, and for understanding how BCR-ABL collaborates with Ikzf1 mutations to generate aggressive B-ALL.
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| Overall design |
RNA-Seq from BCR-ABL+ transformed cells at day 14 of in vitro cell culture comparing wt, Ikaros-ZnF1-/- mutant and Ikaros-ZnF4-/- mutant (2 biological replicates).
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| Contributor(s) |
Schjerven H, Smale ST |
| Citation(s) |
28190001 |
| Submission date |
Jul 06, 2012 |
| Last update date |
May 15, 2019 |
| Contact name |
Hilde Schjerven |
| Organization name |
UCSF
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| Department |
Laboratory Medicine
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| Street address |
513 Parnassus Ave
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| City |
San Francisco |
| State/province |
CA |
| ZIP/Postal code |
94143 |
| Country |
USA |
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| Platforms (1) |
| GPL13112 |
Illumina HiSeq 2000 (Mus musculus) |
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| Samples (6)
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| Relations |
| BioProject |
PRJNA170121 |
| SRA |
SRP014141 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE39160_RAW.tar |
860.5 Mb |
(http)(custom) |
TAR (of BIGWIG) |
| GSE39160_RPKM_d14_BCR_ABL_in_vitro_cultures.txt.gz |
427.7 Kb |
(ftp)(http) |
TXT |
SRA Run Selector |
| Raw data are available in SRA |
| Processed data provided as supplementary file |
| Processed data are available on Series record |
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