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Stage- and cell type-specific requirements of ikzf1 during hematopoietic differentiation in zebrafish [ikaros]

ABSTRACT: The characterisation of two zebrafish ikzf1 mutant lines missing the two C-terminal zinc fingers only and both part of the DNA binding domain plus the C-terminal zinc fingers respectively gives insight into the specific roles of these elements during zebrafish hematopoiesis

ORGANISM(S): Danio rerio

PROVIDER: GSE214952 | GEO | 2022/10/08

REPOSITORIES: GEO

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Stage- and cell type-specific requirements of ikzf1 during hematopoietic differentiation in zebrafish [it325]

Project description:The characterisation of two zebrafish ikzf1 mutant lines missing the two C-terminal zinc fingers only and both part of the DNA binding domain plus the C-terminal zinc fingers respectively gives insight into the specific roles of these elements during zebrafish hematopoiesis

2022-10-08 | GSE214953 | GEO

Stage- and cell type-specific requirements of ikzf1 during haematopoietic differentiation in zebrafish

Project description:The zinc finger transcription factor Ikaros1 (Ikzf1) is required for lymphoid development in mammals. It is characterized by the presence of four zinc fingers in its DNA binding domain and two zinc fingers in the C-terminal protein interaction module. Here, we describe the phenotypes of zebrafish homozygous for two distinct mutant ikzf1 alleles. The IT325 variant lacks the C-terminal two zinc fingers, whereas the fr105 variant retains only the first zinc finger of the DNA binding domain. Our results indicate that an intact ikzf1 gene is required for larval T cell development, whereas low levels of adult lymphoid development recover in the mutants. By contrast, the mutants exhibit a signature of increased myelopoiesis at larval and adult stages. Of note, both mutants stimulate erythroid differentiation in larvae, indicating that the C-terminal zinc fingers negatively regulate the extent of red blood cell production. An unexpected differential effect of the two mutants on adult erythropoiesis suggests a direct requirement of an intact DNA binding domain for entry of progenitors into the red blood cell lineage. Collectively, our results reinforce the biological differences between larval and adult haematopoiesis, indicate a stage-specific function of ikzf1 in regulating the hierarchical bifurcations of differentiation, and assign distinct functions to the DNA binding domain and the C-terminal zinc fingers.

2022-12-09 | GSE200756 | GEO

Stage- and cell type-specific requirements of ikzf1 during hematopoietic differentiation in zebrafish [ikaros]

Project description:Stage- and cell type-specific requirements of ikzf1 during hematopoietic differentiation in zebrafish [ikaros]

| PRJNA887794 | ENA

Stage- and cell type-specific requirements of ikzf1 during hematopoietic differentiation in zebrafish

Project description:Stage- and cell type-specific requirements of ikzf1 during hematopoietic differentiation in zebrafish

| PRJNA887792 | ENA

Stage- and cell type-specific requirements of ikzf1 during haematopoietic differentiation in zebrafish

Project description:Stage- and cell type-specific requirements of ikzf1 during haematopoietic differentiation in zebrafish

| PRJNA826497 | ENA

Efficacy of retinoids in IKZF1-mutated BCR-ABL1 acute lymphoblastic leukemia

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

Stage- and cell type-specific requirements of ikzf1 during hematopoietic differentiation in zebrafish [it325]

Project description:Stage- and cell type-specific requirements of ikzf1 during hematopoietic differentiation in zebrafish [it325]

| PRJNA887793 | ENA

Selective Functions of Individual Zinc Fingers Within the DNA-Binding Domain of Ikaros (ChIP-seq: Thymocytes)

Project description:The C2H2 zinc finger is the most prevalent DNA-binding motif in the mammalian proteome, with DNA-binding domains usually containing more tandem fingers than are needed for stable sequence-specific DNA recognition. To examine the reason for the frequent presence of multiple zinc fingers, we generated mice lacking finger 1 or finger 4 of the 4-finger DNA-binding domain of Ikaros, a critical regulator of lymphopoiesis and leukemogenesis. Each mutant strain exhibited a specific subset of the phenotypes observed with Ikaros null mice. Of particular relevance, fingers 1 and 4 contributed to distinct stages of B- and T-cell development and finger 4 was selectively required for tumor suppression in thymocytes and in a new model of BCR-ABL+ acute lymphoblastic leukemia. These results, combined with transcriptome profiling (this GEO submission: RNA-Seg of whole thymus from wt and the two ZnF mutants), reveal that different subsets of fingers within multi-finger transcription factors can regulate distinct target genes and biological functions, and they demonstrate that selective mutagenesis can facilitate efforts to elucidate the functions and mechanisms of action of this prevalent class of factors. Ikaros ChIP-Seq from Whole Thymus comparing wt, Ikaros-ZnF1-/- mutant and Ikaros-ZnF4-/- mutant

2013-09-08 | E-GEOD-33679 | biostudies-arrayexpress

Tumor Suppressor IKZF1 Mediates Glucocorticoid Therapy Resistance in B Cell Precursor Acute Lymphoblastic Leukemia

Project description:Analysis of the effect of Prednisolone in mouse splenocytes with and without Ikzf1 at gene expression level. The hypothesis tested in the present study was that loss of Ikzf1 affects the induction and repression of the Glucocorticoid receptor target genes. Results provide important information of the differentially expressed genes regulated by Ikzf1 upon Prednisolone treatment, explaining the resistance towards Glucocorticoid-induced apoptosis in splenocytes harboring Ikzf1 loss. Total RNA was obtained from WT and Ikzf1+/- splenocytes subjected to 16 hours Prednsiolone treatment compared to untreated cells.

2015-02-04 | E-GEOD-65554 | biostudies-arrayexpress

Selective Functions of Individual Zinc Fingers Within the DNA-Binding Domain of Ikaros (RNA-seq: sorted DP thymocytes)

Project description:The C2H2 zinc finger is the most prevalent DNA-binding motif in the mammalian proteome, with DNA-binding domains usually containing more tandem fingers than are needed for stable sequence-specific DNA recognition. To examine the reason for the frequent presence of multiple zinc fingers, we generated mice lacking finger 1 or finger 4 of the 4-finger DNA-binding domain of Ikaros, a critical regulator of lymphopoiesis and leukemogenesis. Each mutant strain exhibited a specific subset of the phenotypes observed with Ikaros null mice. Of particular relevance, fingers 1 and 4 contributed to distinct stages of B- and T-cell development and finger 4 was selectively required for tumor suppression in thymocytes and in a new model of BCR-ABL+ acute lymphoblastic leukemia. These results, combined with transcriptome profiling (this GEO submission: RNA-Seg of whole thymus from wt and the two ZnF mutants), reveal that different subsets of fingers within multi-finger transcription factors can regulate distinct target genes and biological functions, and they demonstrate that selective mutagenesis can facilitate efforts to elucidate the functions and mechanisms of action of this prevalent class of factors. Ikaros RNA-Seq from double positive thymocytes comparing wt (n=2), Ikaros-ZnF1-/- mutant (n=2) and Ikaros-ZnF4-/- mutant (n=2)

2013-09-08 | E-GEOD-47496 | biostudies-arrayexpress

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