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Series GSE39160 Query DataSets for GSE39160
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
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.
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).
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
Department Laboratory Medicine
Street address 513 Parnassus Ave
City San Francisco
State/province CA
ZIP/Postal code 94143
Country USA
Platforms (1)
GPL13112 Illumina HiSeq 2000 (Mus musculus)
Samples (6)
GSM957180 BCR-ABL+_wt_d14_repl1
GSM957181 BCR-ABL+_Ikaros_ZnF1-/-_d14_repl1
GSM957182 BCR-ABL+_Ikaros_ZnF4-/-_d14_repl1
BioProject PRJNA170121
SRA SRP014141

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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
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Raw data are available in SRA
Processed data provided as supplementary file
Processed data are available on Series record

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