ZFP91 and IKZF1 Cooperatively Promote IMiD Resistance in T-Cell Lymphomas
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA723579 | ENA |
REPOSITORIES: ENA
Similar Datasets
Project description:The immunomodulatory (IMiD) agents, such as lenalidomide, are highly effective treatment for several B cell lymphomas but have poor efficacy in T cell lymphomas (TCLs). Here, we show that IKZF1 is a key drug target and vulnerability in lenalidomide sensitive TCL cells. However, TCLs are largely resistant and become less dependent on IKZF1. Instead, ZPF91 functions as a transcription factor (TF) and coregulates cell survival with IKZF1 in TCL cells that develop resistance to lenalidomide. Aberrant upregulation of CSNK2B, which leads to c-Jun inactivation, contributes to an enhanced TF activity of ZFP91 and suppresses immune activation triggered by lenalidomide. Although ZFP91 can be better targeted by pomalidomide compared to lenalidomide, an inefficient degradation of IKZF1 and ZFP91 widely exists among IMiD-resistance TCLs. A novel CELMoD agent CC-92480, with markedly increased potency and similar substrate selectivity, can overcome IMiD-resistance across multiple TCL subtypes by near complete degradation of IKZF1 and ZFP91.
2022-04-21 | GSE172505 | GEO
Project description:To obtain further insight into the pathways or specific genes that drive resistance to AraC upon loss of IKZF1, we performed RNAsequencing on samples from wildtype and IKZF1 knockout Sem cells treated with and without AraC
2023-08-31 | GSE234637 | GEO
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
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:Transcription factor partners can cooperatively bind to DNA composite elements to augment gene transcription. Here, we report a novel protein-DNA binding screening pipeline, termed Spacing Preference Identification of Composite Elements (SPICE), that can systematically predict protein binding partners and DNA motif spacing preferences. SPICE de novo predicted known composite elements, including AP1-IRF composite elements (AICE) and STAT5 tetramers, and also predicted a range of novel binding partners, including JUN-IKZF1 composite elements. We confirmed cooperative binding of JUN and IKZF1 to an upstream conserved noncoding region, CNS9, in the human IL10 gene, that contains a non-canonical IKZF1 site, and the activity of an IL10-luciferase reporter construct depended on both this site and the AP1 binding site within this composite element in primary B and T cells. Our findings reveal an unappreciated global association of IKZF1 and AP1, and establish SPICE as a valuable new pipeline for predicting novel transcription binding complexes.
2023-11-05 | GSE230035 | GEO
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.
2015-02-04 | GSE65554 | 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.
2015-09-04 | GSE68391 | GEO
Project description:Immunoglobulin gene rearrangement and somatic hypermutation have the potential to create neoantigens in non-Hodgkin B cell lymphoma. However, the presentation of these putative immunoglobulin neoantigens by B cell lymphomas has not been proven. We used MHC immunoprecipitation followed by liquid chromatography and tandem mass spectrometry (LC-MS/MS) to define antigens presented by follicular lymphomas (FL), chronic lymphocytic leukemias (CLL), diffuse large B cell lymphoma (DLBCL) and mantle cell lymphomas (MCL). We found presentation of the clonal immunoglobulin molecule, including neoantigens by both class I and class II MHC, though more commonly in class II MHC. To determine whether B cell activation could promote presentation of immunoglobulin neoantigens, we used a toll-like receptor 9 (TLR9) agonists to upregulate expression of MHC-II. This resulted in enhanced class II MHC presentation of the immunoglobulin variable region including neoantigens. These findings demonstrate that immunoglobulin neoantigens are presented across most subtypes of B cell lymphomas. Activation of lymphoma cells to upregulate antigen presentation boosts presentation of immunoglobulin neoantigens and represents a strategy for augmenting lymphoma immunotherapies.
2019-01-07 | PXD010808 | Pride
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 | GSE54821 | 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