Nuclear FOXO1 promotes lymphomagenesis in germinal center B cells
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE119437 | GEO | 2018/12/21
REPOSITORIES: GEO
Similar Datasets
Project description:FOXO1 has an oncogenic role in adult germinal center derived lymphomas, in which mutations, predominately within the AKT recognition motif, cause nuclear retention of FOXO1 resulting in increased cell proliferation. To determine the prevalence and distribution of FOXO1 mutations in pediatric Burkitt lymphoma (BL), we sequenced a large number of sporadic and endemic BL patient samples. We report a high frequency of FOXO1 mutations in both sporadic and endemic BL at diagnosis, occurring in 23/78 (29%) and 48/89 (54%) samples respectively, as well as 8/16 (50%) cases at relapse. Mutations of T24 were the most common in sporadic BL but were rare in endemic cases, in which mutations of residue S22, also within the AKT recognition motif, were the most frequent. FOXO1 mutations were almost always present in the major tumor cell clone but were not associated with outcome. Analysis of other recurrent mutations reported in BL revealed that FOXO1 mutations were associated with mutations of DDX3X and ARID1A, but not MYC, TCF3/ID3 or members of the phosphatidylinositol 3’ OH kinase (PI3K) signaling pathway. We further show common nuclear retention of the FOXO1 protein, irrespective of mutation status, suggesting alternative unknown mechanisms for maintaining FOXO1 transcriptional activity in BL. CRISPR/Cas9 knockout of FOXO1 in an endemic cell line produced a significant decrease in cell proliferation, supporting an oncogenic role for FOXO1 in endemic BL. Thus, FOXO1 is frequently mutated in both sporadic and endemic BL and may offer a potential therapeutic target for pediatric BL patients worldwide.
| EGAS00001003719 | EGA
Project description:In Burkitt lymphoma (BL), an aggressive germinal-center (GC) derived non-Hodgkin B-cell lymphoma characterized by MYC translocations as early transforming event, the apoptotic properties of MYC must have been overcome by pro-survival signals. Whereas activation of the pro-survival factor NFkappaB is not eminent in BL, PI3K signalling, which mediates B cell receptor associated survival signals in mature B cells, might be the cooperating event. Here we prove this hypothesis by the generation of BL in mice upon concordant expression of MYC and activation of PI3K in GC B cells. Unlike existing murine BL-like models, our tumour model fully phenocopies primary human BL and reflects the complexity of the disease with regard to histological appearance, surface marker expression, and characteristic gene expression profiles. Like in human BL, tumour monoclonality indicated a multistep pathogenesis underlining MYC and PI3K as predisposing events that invariably lead to GC-derived BL formation. In accordance, copy number alteration analysis revealed genomic regions involved in BL pathogenesis.
2012-08-14 | GSE35219 | GEO
Project description:In Burkitt lymphoma (BL), an aggressive germinal-center (GC) derived non-Hodgkin B-cell lymphoma characterized by MYC translocations as early transforming event, the apoptotic properties of MYC must have been overcome by pro-survival signals. Whereas activation of the pro-survival factor NFkappaB is not eminent in BL, PI3K signalling, which mediates B cell receptor associated survival signals in mature B cells, might be the cooperating event. Here we prove this hypothesis by the generation of BL in mice upon concordant expression of MYC and activation of PI3K in GC B cells. Unlike existing murine BL-like models, our tumour model fully phenocopies primary human BL and reflects the complexity of the disease with regard to histological appearance, surface marker expression, and characteristic gene expression profiles. Like in human BL, tumour monoclonality indicated a multistep pathogenesis underlining MYC and PI3K as predisposing events that invariably lead to GC-derived BL formation. In accordance, copy number alteration analysis revealed genomic regions involved in BL pathogenesis. All samples were obtained from murine lymphomas (Cgamma1-cre; R26StopFLMYC;R26StopFLP110* animals). Cells used for microarray analysis were sorted reporter positive cells. Tumour cells were compared to a matched germline DANN sample to identify acquired aberrations.
2012-08-13 | E-GEOD-35219 | biostudies-arrayexpress
Project description:PI3K signaling and FOXO transcription factors play opposing roles at several B cell developmental stages. We show here abundant nuclear FOXO1 expression in the proliferative compartment of the germinal center (GC), its dark zone (DZ), and PI3K activity, downregulating FOXO1, in the GC light zone (LZ), where cells are selected for further differentiation. However, here FOXO1 is expressed in c-Myc+ cells destined for DZ reentry. Upon FOXO1 ablation by genetic means or induction of PI3K activity GCs become devoid of their DZ, due at least partly to the downregulation of the chemokine receptor CXCR4. While this is known to prevent proper cyclic selection of cells expressing high-affinity antibodies, the initiation of immunoglobulin switching is essentially dependent on FOXO1 activity. All samples were obtained from mouse germinal center (GC) B cells (Cgamma1-cre; YFP, P110*, FOXO1 f/f or PTEN f/f animals). Cells used for microarray analysis were FACS sorted cells.
2015-11-23 | E-GEOD-68043 | biostudies-arrayexpress
Project description:PI3K signaling and FOXO transcription factors play opposing roles at several B cell developmental stages. We show here abundant nuclear FOXO1 expression in the proliferative compartment of the germinal center (GC), its dark zone (DZ), and PI3K activity, downregulating FOXO1, in the GC light zone (LZ), where cells are selected for further differentiation. However, here FOXO1 is expressed in c-Myc+ cells destined for DZ reentry. Upon FOXO1 ablation by genetic means or induction of PI3K activity GCs become devoid of their DZ, due at least partly to the downregulation of the chemokine receptor CXCR4. While this is known to prevent proper cyclic selection of cells expressing high-affinity antibodies, the initiation of immunoglobulin switching is essentially dependent on FOXO1 activity.
2015-11-23 | GSE68043 | GEO
Project description:The transcription factor FOXO1 directs germinal center (GC) polarity and supports affinity maturation by silencing immune activation programs in GC B cells. Recurrent somatic mutations in GC-derived B cell non-Hodgkin lymphomas (B-NHL) often target and reportedly activate FOXO1 by preventing its negative regulation by PI3K. Herein, using ad hoc mouse models, engineered cell lines and primary tumor specimens, we show instead that FOXO1 mutant proteins display altered transcriptional activities suggestive of partial loss-of-function. These defects drive simultaneous hyperactivation of signaling pathways (Stress Activated Protein Kinase -SAPK/JNK, Phosphoinositide 3-kinase -PI3K/AKT) and gene expression programs typically activated in GC B cells upon positive selection. Such changes confer mutant B cells with competitive advantages in response to key immune signals, leading to abnormal amplification of GC responses. Evidence of these FOXO1 ‘mutant’ gene programs can be found in a fraction of human B-NHL and predict clinical outcome, thus implying the frequent co-option of positive selection programs during GC-derived B-NHL pathogenesis.
2021-07-30 | GSE143774 | GEO
Project description:The transcription factor FOXO1 directs germinal center (GC) polarity and supports affinity maturation by silencing immune activation programs in GC B cells. Recurrent somatic mutations in GC-derived B cell non-Hodgkin lymphomas (B-NHL) often target and reportedly activate FOXO1 by preventing its negative regulation by PI3K. Herein, using ad hoc mouse models, engineered cell lines and primary tumor specimens, we show instead that FOXO1 mutant proteins display altered transcriptional activities suggestive of partial loss-of-function. These defects drive simultaneous hyperactivation of signaling pathways (Stress Activated Protein Kinase -SAPK/JNK, Phosphoinositide 3-kinase -PI3K/AKT) and gene expression programs typically activated in GC B cells upon positive selection. Such changes confer mutant B cells with competitive advantages in response to key immune signals, leading to abnormal amplification of GC responses. Evidence of these FOXO1 ‘mutant’ gene programs can be found in a fraction of human B-NHL and predict clinical outcome, thus implying the frequent co-option of positive selection programs during GC-derived B-NHL pathogenesis.
2021-07-30 | GSE143773 | GEO
Project description:The transcription factor FOXO1 directs germinal center (GC) polarity and supports affinity maturation by silencing immune activation programs in GC B cells. Recurrent somatic mutations in GC-derived B cell non-Hodgkin lymphomas (B-NHL) often target and reportedly activate FOXO1 by preventing its negative regulation by PI3K. Herein, using ad hoc mouse models, engineered cell lines and primary tumor specimens, we show instead that FOXO1 mutant proteins display altered transcriptional activities suggestive of partial loss-of-function. These defects drive simultaneous hyperactivation of signaling pathways (Stress Activated Protein Kinase -SAPK/JNK, Phosphoinositide 3-kinase -PI3K/AKT) and gene expression programs typically activated in GC B cells upon positive selection. Such changes confer mutant B cells with competitive advantages in response to key immune signals, leading to abnormal amplification of GC responses. Evidence of these FOXO1 ‘mutant’ gene programs can be found in a fraction of human B-NHL and predict clinical outcome, thus implying the frequent co-option of positive selection programs during GC-derived B-NHL pathogenesis.
2021-07-30 | GSE143772 | GEO
Project description:We found that FOXO1 knock-down inhibits cell cycle progression in Burkitt's lymphoma (BL) cell lines BL41 and Namalwa.
2018-12-31 | GSE109911 | GEO
Project description:Our previous study reported that IGFBP7 plays a role in maintaining mRNA stability of oncogenic lncRNA UBE2CP3 by RNA-RNA interaction. Clinical cohort studies had implied an oncogenic role of IGFBP7 in GC. However, the molecular mechanism of IGFBP7 in driving gastric cancer (GC) progression remains unknown. In this study, clinical analysis based on two independent cohort showed that IGFBP7 was positively associated with poor prognosis and macrophage infiltration in GC. Loss-of-function studies confirmed the oncogenic properties of IGFBP7 in regulating GC cell proliferation and invasion. Mechanismly, IGFBP7 was induced by epithelial-to-mesenchymal transition (EMT) signaling, since its expression was increased by TGF-beta treatment and reduced by overexpression of OVOL2 in GC. RNA sequencing, qRT-PCR, ELISA assay showed that IGFBP7 positively regulating FGF2 expression and secretion. Transcriptome analysis revealed that FGFR1 was downregulated in M1 macrophages but upregulated in M2 macrophages. Exogenous recombinant IGFBP7 protein in macrophages and GC cells further identified that IGFBP7 promotes macrophage polarization towards to a M2/TAM phenotype via FGF2/FGFR1/PI3K/AKT axis. Our finding highlights that IGFBP7 promotes GC by enhancing TAM infiltration through FGF2/FGFR1/PI3K/AKT axis.
2022-07-08 | GSE207373 | GEO