Antagonism of B cell enhancer networks by STAT5 drives leukemia and poor patient survival
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE25643 | GEO | 2016/11/30
SECONDARY ACCESSION(S): PRJNA133897
REPOSITORIES: GEO
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Project description:The transcription factor STAT5 plays a critical role in B cell Acute Lymphoblastic Leukemia (B-ALL). How STAT5 mediates this effect is unclear. Here we demonstrate that STAT5 activation cooperates with defects in the pre-BCR signaling components Blnk, Btk, Prkcb, Nfkb1, and Ikzf1 to initiate B-ALL. STAT5 antagonizes NFkB and IKAROS by opposing regulation of shared target genes. STAT5 binding was enriched at super-enhancers, which were associated with an opposing network of transcription factors, including PAX5, EBF1, PU.1, IRF4, and IKAROS. Patients with high ratios of active STAT5 to NFκB or IKAROS have more aggressive disease. Our studies illustrate that an imbalance of two opposing transcriptional programs drive B-ALL, and suggest that restoring the balance of these pathways may inhibit B-ALL.
2017-04-03 | GSE86878 | GEO
Project description:Skeletal muscle atrophy is a debilitating condition associated with weakness, fatigue, and reduced functional capacity. Nuclear factor-kappaB (NF-κB) transcription factors play a critical role in atrophy. Knockout of genes encoding p50 or the NF-κB co-transactivator, Bcl-3, abolish disuse atrophy and thus they are NF-κB factors required for disuse atrophy. We do not know however, the genes targeted by NF-κB that produce the atrophied phenotype. Here we identify the genes required to produce disuse atrophy using gene expression profiling in wild type compared to Nfkb1 (gene encodes p50) and Bcl-3 deficient mice. There were 185 and 240 genes upregulated in wild type mice due to unloading, that were not upregulated in Nfkb1-/- and Bcl-3-/- mice, respectively, and so these genes were considered direct or indirect targets of p50 and Bcl-3. All of the p50 gene targets were contained in the Bcl-3 gene target list. Most genes were involved with protein degradation, signaling, translation, transcription, and transport. To identify direct targets of p50 and Bcl-3 we performed chromatin immunoprecipitation of selected genes previously shown to have roles in atrophy. Trim63 (MuRF1), Fbxo32 (MAFbx), Ubc, Ctsl, Runx1, Tnfrsf12a (Tweak receptor), and Cxcl10 (IP-10) showed increased Bcl-3 binding to κB sites in unloaded muscle and thus were direct targets of Bcl-3. p50 binding to the same sites on these genes either did not change or increased, supporting the idea of p50:Bcl-3 binding complexes. p65 binding to κB sites showed decreased or no binding to these genes with unloading. Fbxo9, Psma6, Psmc4, Psmg4, Foxo3, Ankrd1 (CARP), and Eif4ebp1 did not show changes in p65, p50, or Bcl-3 binding to κB sites, and so were considered indirect targets of p50 and Bcl-3. This work represents the first study to use a global approach to identify genes required to produce the atrophied phenotype with disuse. 24 mice were used based on 4 mice per group, 3 mouse genotypes (wild type, Nfkb1-/-, Bcl3-/-) and 2 conditions (weight-bearing and unloaded).
2011-01-10 | E-GEOD-23497 | biostudies-arrayexpress
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: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: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 | GSE247279 | GEO
Project description:The zinc-finger transcription factor Ikaros (Ikzf1) modulates key gene expression programs important for hematopoietic development, and coding mutations in IKZF1 are found in patients with immunodeficiency, leukemia, and autoimmunity. While Ikaros has a well-established function in hematopoiesis, its role in other cell types is less well defined. Here, we uncover new functions for Ikaros in thymic epithelial lineage development and show that Ikzf1 expression in medullary thymic epithelial cells (mTECs) is required for both Autoimmune Regulator positive (Aire+) mTEC development and tissue-specific antigen (TSA) gene expression. Accordingly, TEC-specific deletion of Ikzf1 in mice results in a profound decrease in Aire+ mTECs, a global loss of TSA gene expression, and the development of autoimmunity. Moreover, Ikaros shapes thymic mimetic cell diversity and its deletion results in a dramatic expansion of thymic tuft cells and muscle-like mTECs and a loss of other Aire-dependent mimetic populations. Single-cell analysis reveals Ikaros modulates core transcriptional programs in TECs that correlate with the observed cellular changes. Our findings highlight a previously undescribed role for Ikaros in regulating epithelial lineage development and function, and suggest that failed thymic central tolerance could contribute to the autoimmunity seen in humans with IKZF1 mutations.
2023-10-25 | GSE241742 | GEO
Project description:The zinc-finger transcription factor Ikaros (Ikzf1) modulates key gene expression programs important for hematopoietic development, and coding mutations in IKZF1 are found in patients with immunodeficiency, leukemia, and autoimmunity. While Ikaros has a well-established function in hematopoiesis, its role in other cell types is less well defined. Here, we uncover new functions for Ikaros in thymic epithelial lineage development and show that Ikzf1 expression in medullary thymic epithelial cells (mTECs) is required for both Autoimmune Regulator positive (Aire+) mTEC development and tissue-specific antigen (TSA) gene expression. Accordingly, TEC-specific deletion of Ikzf1 in mice results in a profound decrease in Aire+ mTECs, a global loss of TSA gene expression, and the development of autoimmunity. Moreover, Ikaros shapes thymic mimetic cell diversity and its deletion results in a dramatic expansion of thymic tuft cells and muscle-like mTECs and a loss of other Aire-dependent mimetic populations. Single-cell analysis reveals Ikaros modulates core transcriptional programs in TECs that correlate with the observed cellular changes. Our findings highlight a previously undescribed role for Ikaros in regulating epithelial lineage development and function, and suggest that failed thymic central tolerance could contribute to the autoimmunity seen in humans with IKZF1 mutations.
2023-10-25 | GSE238149 | GEO
Project description:The zinc-finger transcription factor Ikaros (Ikzf1) modulates key gene expression programs important for hematopoietic development, and coding mutations in IKZF1 are found in patients with immunodeficiency, leukemia, and autoimmunity. While Ikaros has a well-established function in hematopoiesis, its role in other cell types is less well defined. Here, we uncover new functions for Ikaros in thymic epithelial lineage development and show that Ikzf1 expression in medullary thymic epithelial cells (mTECs) is required for both Autoimmune Regulator positive (Aire+) mTEC development and tissue-specific antigen (TSA) gene expression. Accordingly, TEC-specific deletion of Ikzf1 in mice results in a profound decrease in Aire+ mTECs, a global loss of TSA gene expression, and the development of autoimmunity. Moreover, Ikaros shapes thymic mimetic cell diversity and its deletion results in a dramatic expansion of thymic tuft cells and muscle-like mTECs and a loss of other Aire-dependent mimetic populations. Single-cell analysis reveals Ikaros modulates core transcriptional programs in TECs that correlate with the observed cellular changes. Our findings highlight a previously undescribed role for Ikaros in regulating epithelial lineage development and function, and suggest that failed thymic central tolerance could contribute to the autoimmunity seen in humans with IKZF1 mutations.
2023-10-25 | GSE238148 | GEO