Stage-specific control of early B cell development by the transcription factor Ikaros
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE53595 | GEO | 2014/02/09
SECONDARY ACCESSION(S): PRJNA232466
REPOSITORIES: GEO
Similar Datasets
Project description:Ikaros is an essential regulator of lymphopoiesis. Here, we studied the B-cell-specific function of Ikaros by conditional Ikzf1 inactivation in pro-B cells. B-cell development was arrested at an aberrant ‘pro-B’ cell stage characterized by increased cell adhesion and loss of pre-B cell receptor signaling. Ikaros was found to activate genes coding for pre-BCR signal transducers and to repress genes involved in the downregulation of pre-BCR signaling and upregulation of the integrin signaling pathway. Unexpectedly, derepression of Aiolos expression could not compensate for the loss of Ikaros in pro-B cells. Ikaros differentially controlled active chromatin at promoters and enhancers of repressed and activated target genes. Notably, Ikaros binding and target gene expression was dynamically regulated at distinct stages of early B-lymphopoiesis. 16 RNA-Seq samples in pre-proB cells (4 replicates, for each 2 controls and 2 experimental samples); 4 RNA-Seq samples in pro-B cells in Rag2-/- backgrounds (Ikzf1 deleted versus non deleted, 2 replicates each); 4 RNA-Seq samples in c-Kit high pro-B cells (Ikzf1 deleted versus non deleted, 2 replicates each); 4 RNA-Seq samples in pro-B cells (Ikzf1 deleted versus non deleted, 2 replicates each); 2 RNA-Seq samples pre-B cells wild type; 8 chromatin ChIP-Seq samples (4x H3K9ac, 4x H3K4me3, Ikzf1 deleted/non deleted, two replicates each).; 4 Transcription factor ChIP-Seq samples in pro-B cells; 1 Transcription factor ChIP-Seq samples in DP-T cells; 1 Transcription factor ChIP-Seq samples in pre-pro-B cells; 2 Mi-2b Chip-Seq samples (Ikzf1 deleted versus non deleted); 1 ChIP-Seq input track for pro-B cells; 1 ChIP-Seq input track for DP-T cells
2014-02-09 | E-GEOD-53595 | 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:Ikaros family transcription factors regulate lymphocyte biology and are targets of the immunomodulatory imide drugs (IMiDs) for hematological malignancies. Ikaros (Ikzf1/IKZF1) is the most broadly expressed family member in lymphocytes, yet its role in innate lymphopoiesis is unknown. Here we used gene inactivation to reveal that NK cell-expression of Ikaros is essential for normal NK lymphopoiesis. Mechanistically, IKZF1 directly repressed Cish and Socs2, known negative regulators of IL-15R resulting in impaired IL-15 signaling in Ikzf1-null NK cells. Bcl2l11/BIM levels and apoptosis were increased in Ikzf1-null NK cells which in part accounted for the NK lymphopenia since both apoptosis and NK cell frequency were restored to normal levels when Ikzf1 and Bcl2l11 were co-deleted. Ikzf1-null NK cells presented extensive transcriptional alterations with a striking reduction in expression of genes encoding AP-1 transcriptional complexes (Fos/Jun members) and a compensatory increase in Ikzf2 and Ikzf3. Both IKZF1 and IKZF3 directly bound AP-1 family members and deletion of both Ikzf1 and Ikzf3 in NK cells resulted in a further reduction in Jun/Fos expression and a complete loss of peripheral NK cells in mice. Consistently, IKZF1 bound Jun/Fos genes at the same locations in activated B cells identifying a novel and conserved role for IKZF1 in Jun/Fos regulation. Collectively we show the Ikaros-family are novel regulators of apoptosis, cytokine responsiveness and AP-1 transcriptional activity required for NK cell development and function.
2023-11-08 | GSE247279 | GEO
Project description:Ikaros family transcription factors regulate lymphocyte biology and are targets of the immunomodulatory imide drugs (IMiDs) for hematological malignancies. Ikaros (Ikzf1/IKZF1) is the most broadly expressed family member in lymphocytes, yet its role in innate lymphopoiesis is unknown. Here we used gene inactivation to reveal that NK cell-expression of Ikaros is essential for normal NK lymphopoiesis. Mechanistically, IKZF1 directly repressed Cish and Socs2, known negative regulators of IL-15R resulting in impaired IL-15 signaling in Ikzf1-null NK cells. Bcl2l11/BIM levels and apoptosis were increased in Ikzf1-null NK cells which in part accounted for the NK lymphopenia since both apoptosis and NK cell frequency were restored to normal levels when Ikzf1 and Bcl2l11 were co-deleted. Ikzf1-null NK cells presented extensive transcriptional alterations with a striking reduction in expression of genes encoding AP-1 transcriptional complexes (Fos/Jun members) and a compensatory increase in Ikzf2 and Ikzf3. Both IKZF1 and IKZF3 directly bound AP-1 family members and deletion of both Ikzf1 and Ikzf3 in NK cells resulted in a further reduction in Jun/Fos expression and a complete loss of peripheral NK cells in mice. Consistently, IKZF1 bound Jun/Fos genes at the same locations in activated B cells identifying a novel and conserved role for IKZF1 in Jun/Fos regulation. Collectively we show the Ikaros-family are novel regulators of apoptosis, cytokine responsiveness and AP-1 transcriptional activity required for NK cell development and function.
2023-11-08 | GSE247280 | GEO
Project description:Ikaros family transcription factors regulate lymphocyte biology and are targets of the immunomodulatory imide drugs (IMiDs) for hematological malignancies. Ikaros (Ikzf1/IKZF1) is the most broadly expressed family member in lymphocytes, yet its role in innate lymphopoiesis is unknown. Here we used gene inactivation to reveal that NK cell-expression of Ikaros is essential for normal NK lymphopoiesis. Mechanistically, IKZF1 directly repressed Cish and Socs2, known negative regulators of IL-15R resulting in impaired IL-15 signaling in Ikzf1-null NK cells. Bcl2l11/BIM levels and apoptosis were increased in Ikzf1-null NK cells which in part accounted for the NK lymphopenia since both apoptosis and NK cell frequency were restored to normal levels when Ikzf1 and Bcl2l11 were co-deleted. Ikzf1-null NK cells presented extensive transcriptional alterations with a striking reduction in expression of genes encoding AP-1 transcriptional complexes (Fos/Jun members) and a compensatory increase in Ikzf2 and Ikzf3. Both IKZF1 and IKZF3 directly bound AP-1 family members and deletion of both Ikzf1 and Ikzf3 in NK cells resulted in a further reduction in Jun/Fos expression and a complete loss of peripheral NK cells in mice. Consistently, IKZF1 bound Jun/Fos genes at the same locations in activated B cells identifying a novel and conserved role for IKZF1 in Jun/Fos regulation. Collectively we show the Ikaros-family are novel regulators of apoptosis, cytokine responsiveness and AP-1 transcriptional activity required for NK cell development and function.
2023-11-08 | GSE247282 | GEO
Project description:Ikaros family transcription factors regulate lymphocyte biology and are targets of the immunomodulatory imide drugs (IMiDs) for hematological malignancies. Ikaros (Ikzf1/IKZF1) is the most broadly expressed family member in lymphocytes, yet its role in innate lymphopoiesis is unknown. Here we used gene inactivation to reveal that NK cell-expression of Ikaros is essential for normal NK lymphopoiesis. Mechanistically, IKZF1 directly repressed Cish and Socs2, known negative regulators of IL-15R resulting in impaired IL-15 signaling in Ikzf1-null NK cells. Bcl2l11/BIM levels and apoptosis were increased in Ikzf1-null NK cells which in part accounted for the NK lymphopenia since both apoptosis and NK cell frequency were restored to normal levels when Ikzf1 and Bcl2l11 were co-deleted. Ikzf1-null NK cells presented extensive transcriptional alterations with a striking reduction in expression of genes encoding AP-1 transcriptional complexes (Fos/Jun members) and a compensatory increase in Ikzf2 and Ikzf3. Both IKZF1 and IKZF3 directly bound AP-1 family members and deletion of both Ikzf1 and Ikzf3 in NK cells resulted in a further reduction in Jun/Fos expression and a complete loss of peripheral NK cells in mice. Consistently, IKZF1 bound Jun/Fos genes at the same locations in activated B cells identifying a novel and conserved role for IKZF1 in Jun/Fos regulation. Collectively we show the Ikaros-family are novel regulators of apoptosis, cytokine responsiveness and AP-1 transcriptional activity required for NK cell development and function.
2023-11-08 | GSE247281 | GEO
Project description:Deletion of the Ikaros DNA-binding domain generates dominant-negative isoforms that interfere with Ikaros family activity and correlate with poor prognosis in human precursor B cell acute lymphoblastic leukemias (B-ALL). Here, we show that conditional inactivation of the Ikaros DNA binding domain in early pre-B cells arrests their differentiation at a stage where integrin-dependent niche adhesion augments mitogen-activated protein kinase signaling, proliferation, and self-renewal, and attenuates pre-B cell receptor signaling and differentiation. Transplantation of polyclonal Ikzf1 mutant pre-B cells results in long-latency oligoclonal pre-B-ALL, demonstrating that loss of Ikaros contributes to multistep B-leukemogenesis. These results explain how normal pre-B cells transit from a highly proliferative and stromal-dependent to a stromal-independent phase where differentiation is enabled, providing potential therapeutic strategies for IKZF1 mutant B-ALL. One of the analyses described in this manuscript is the differential gene expression of large preB cells sorted from the bone marrow of WT and IKDN mice. The RNASeq method and Deseq analysis algorithm were employed
2014-02-09 | E-GEOD-53401 | biostudies-arrayexpress
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:BCR-ABL1 lymphoblastic leukaemia is characterized by the deletion of Ikaros. The Philadelphia chromosome, encoding BCR-ABL1, is the defining lesion of chronic myelogenous leukemia (CML) and a subset of acute lymphoblastic leukemia (ALL) cases. To define oncogenic lesions that cooperate with BCR-ABL1 to induce ALL, we performed genome-wide analysis of leukemic samples from 23 CML cases and 304 ALL cases, including 43 BCR-ABL1 B-ALL cases. IKZF1 (encoding the transcription factor Ikaros) was deleted in 83.7% of BCR-ABL1 B-ALL cases, but not in chronic phase CML. Deletion of IKZF1 was also identified as an acquired lesion in lymphoid blast crisis of CML. The IKZF1 deletions resulted in haploinsufficiency, expression of a dominant negative Ikaros isoform or the complete loss of Ikaros expression. Sequencing of IKZF1 deletion breakpoints suggested that aberrant V(D)J recombination is responsible for the deletions. These findings suggest that genetic lesions resulting in the loss of Ikaros function are a key event in the development of BCR-ABL1 ALL. *** Due to privacy concerns, the primary SNP array data is no longer available with unrestricted access. Individuals wishing to obtain this data for research purposes may request access using the Web links below. *** This SuperSeries is composed of the SubSeries listed below.
2009-09-02 | GSE9113 | GEO
Project description:Deletion of the Ikaros DNA-binding domain generates dominant-negative isoforms that interfere with Ikaros family activity and correlate with poor prognosis in human precursor B cell acute lymphoblastic leukemias (B-ALL). Here, we show that conditional inactivation of the Ikaros DNA binding domain in early pre-B cells arrests their differentiation at a stage where integrin-dependent niche adhesion augments mitogen-activated protein kinase signaling, proliferation, and self-renewal, and attenuates pre-B cell receptor signaling and differentiation. Transplantation of polyclonal Ikzf1 mutant pre-B cells results in long-latency oligoclonal pre-B-ALL, demonstrating that loss of Ikaros contributes to multistep B-leukemogenesis. These results explain how normal pre-B cells transit from a highly proliferative and stromal-dependent to a stromal-independent phase where differentiation is enabled, providing potential therapeutic strategies for IKZF1 mutant B-ALL.
2014-02-09 | GSE53401 | GEO