Genetic analysis of Ikaros target genes and tumor suppressor function in BCR-ABL1+ pre-B ALL [ATAC-Seq]
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE90666 | GEO | 2017/02/06
SECONDARY ACCESSION(S): PRJNA355312
REPOSITORIES: GEO
Similar Datasets
Project description:ChIP-seq was performed in patient-derived BCR-ABL1+ (Ph+) pre-B ALL cells that harbor heterozygote deletions of the IKZF1 DNA binding domain (Ik6), using cells that inducibly express wild-type Ikaros (Ik1) or an empty vector control.
2017-02-06 | GSE90656 | GEO
Project description:RNA-seq was performed in human Ph+ pre-B ALL cells that harbor a deletion of the Ikaros DNA binding domain (Ik6) after doxycycline induction of exogenous expression of wild-type Ikaros (Ik1) or control empty vector over 0, 12, 24 and 48 hours. Biological replicates (n=2) using independent cultures and inductions were performed.
2017-02-06 | GSE90659 | GEO
Project description:Alterations of IKZF1, encoding the lymphoid transcription factor IKAROS, are a hallmark of high risk acute lymphoblastic leukemia (ALL), however the role of IKZF1 alterations in ALL pathogenesis is poorly understood. Here we show that in mouse models of BCR-ABL1 leukemia, Ikzf1 and Arf alterations synergistically promote the development of an aggressive lymphoid leukemia. Ikzf1 alterations were associated with acquisition of stem cell-like features, including self-renewal and increased bone marrow stromal adhesion. Rexinoid receptor agonists reversed this phenotype, in part by inducing expression of IKZF1, resulting in abrogation of adhesion and self-renewal, cell cycle arrest and attenuation of proliferation without direct cytotoxicity. Retinoids potentiated the activity of dasatinib in mouse and human BCR-ABL1 ALL, providing a new therapeutic option in IKZF1-mutated ALL. Significance: The outcome of therapy for high-risk acute lymphoblastic leukemia remains suboptimal despite contemporary chemotherapy and the advent of targeted therapeutic approaches. Recent genomic studies have identified deletions or mutations of IKZF1 as a hallmark of high-risk ALL, but an understanding of how IKZF1 alteration contribute to leukemia development are lacking. Here we show that IKZF1 alterations drive lymphoid lineage, a stem cell-like phenotype, abnormal bone marrow adhesion, and poor responsiveness to tyrosine kinase inhibitor (TKI) therapy. Using a high-content screen, we show that retinoids reverse this phenotype in part by inducing expression of wild type IKZF1, and increase responsiveness to TKIs. These findings provide new insight into the pathogenesis of high-risk ALL and potential new therapeutic approaches. Pre-B mRNA profiles of p185 MIG and IK6 cells, DMSO or drug treated, in 3 or 4 replicates, using Illumina HiSeq 2500.
2015-09-04 | E-GEOD-68391 | biostudies-arrayexpress
Project description: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.
2017-02-06 | GSE39160 | GEO
Project description:Analysis of lineage depleted human cord blood cells sequentially transduced with retro- (BCR-ABL1) and lentiviral (Ik6) vectors and the corresponding controls. Results provide important informations on the collaboration of BCR-ABL1 and Ik6 in human hematopoietic cells.
2014-05-23 | GSE45452 | GEO
Project description:In order to investigate the function of IKZF1 in ALL, we isolated bone marrow cells from C57Bl6 mice and transformed them with BCR-ABL1. In a second transduction the BCR-ABL1 driven pre-B cells were transformed either with IKZF1-GFP or empty vector control (GFP) and subjected to gene expression analysis.
2013-11-22 | GSE30860 | GEO
Project description:Analysis of lineage depleted human cord blood cells sequentially transduced with retro- (BCR-ABL1) and lentiviral (Ik6) vectors and the corresponding controls. Results provide important informations on the collaboration of BCR-ABL1 and Ik6 in human hematopoietic cells. Double-transduced lineage depleted human cord blood cells were puirifed according to GFP and LNGFR expression. RNA was extracted from purified cells.
2014-05-23 | E-GEOD-45452 | biostudies-arrayexpress
Project description:To examine Ikaros tumor suppressor mechanisms, we have utilized inducible RNAi to dynamically restore endogenous Ikaros expression in BCR-ABL1+ B-ALL driven by its knockdown (Ikaros knockdown), and compared these tumors to tumors driven by BCR-ABL1 alone (control). Restoration of Ikaros causes rapid regression of tumor cells in vivo, significantly prolonging tumor transplant recipient survival. Using both transgenic and retroviral approaches, we conducted expression analysis of B-ALL by RNA-Seq and have identified a series of Ikaros-regulated genes within established tumor cell in vivo. Comparison of Ikaros-activated and Ikaros-repressed genes with human B-ALL expression data shows a set of conserved Ikaros target genes, some of which are associated with patient outcome (namely, CTNND1, IFITM3 and EMP1).
2016-12-11 | GSE75976 | GEO
Project description:We used microarrays to analyze gene expression changes in the Ikaros null ILC87 T cell tumor line after re-expression of Ikaros. ILC87 cells were transduced to stably express the 4-hydroxytamoxifen-inducible (4OHT) Ikaros1-ER fusion protein. ILC87-Ik1-ER cells were treated with mock (EtOH) or 4OHT for 1 day and the global gene expression changes were assessed by microarray analysis.
2015-11-03 | E-GEOD-72801 | biostudies-arrayexpress
Project description:Alterations of IKZF1, encoding the lymphoid transcription factor IKAROS, are a hallmark of high risk acute lymphoblastic leukemia (ALL), however the role of IKZF1 alterations in ALL pathogenesis is poorly understood. Here we show that in mouse models of BCR-ABL1 leukemia, Ikzf1 and Arf alterations synergistically promote the development of an aggressive lymphoid leukemia. Ikzf1 alterations were associated with acquisition of stem cell-like features, including self-renewal and increased bone marrow stromal adhesion. Rexinoid receptor agonists reversed this phenotype, in part by inducing expression of IKZF1, resulting in abrogation of adhesion and self-renewal, cell cycle arrest and attenuation of proliferation without direct cytotoxicity. Retinoids potentiated the activity of dasatinib in mouse and human BCR-ABL1 ALL, providing a new therapeutic option in IKZF1-mutated ALL. Significance: The outcome of therapy for high-risk acute lymphoblastic leukemia remains suboptimal despite contemporary chemotherapy and the advent of targeted therapeutic approaches. Recent genomic studies have identified deletions or mutations of IKZF1 as a hallmark of high-risk ALL, but an understanding of how IKZF1 alteration contribute to leukemia development are lacking. Here we show that IKZF1 alterations drive lymphoid lineage, a stem cell-like phenotype, abnormal bone marrow adhesion, and poor responsiveness to tyrosine kinase inhibitor (TKI) therapy. Using a high-content screen, we show that retinoids reverse this phenotype in part by inducing expression of wild type IKZF1, and increase responsiveness to TKIs. These findings provide new insight into the pathogenesis of high-risk ALL and potential new therapeutic approaches.
2015-09-04 | GSE68391 | GEO