IL-6 promotes MYC-induced B cell lymphomagenesis independent of STAT3
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ABSTRACT:
PROVIDER: PRJNA693547 | ENA |
REPOSITORIES: ENA
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Project description:The inflammatory cytokine IL-6 is known to play a causal role in the promotion of cancer, although the underlying mechanisms remain to be completely understood. Interplay between endogenous and environmental cues determines the fate of cancer development. The Eμ-myc transgenic mouse expresses elevated levels of c-Myc in the B cell lineage and develops B cell lymphomas with associated mutations in p53 or other genes linked to apoptosis. We generated Eμ-myc mice that either lacked the IL-6 gene, or lacked the STAT3 gene specifically in B cells to determine the role of the IL-6/JAK/STAT3 pathway in tumor development. Using the Eμ-myc lymphoma mouse model, we demonstrate that IL-6 is a critical tumor promoter during early stages of B cell lymphomagenesis. IL-6 is shown to inhibit the expression of tumor suppressors, notably BIM and PTEN, thereby advancing MYC-driven B cell tumorigenesis. Several miRNAs known to target BIM and PTEN are upregulated by IL-6 and likely lead to the stable suppression of pro-apoptotic pathways early during the tumorigenic process. STAT3, a classical downstream effector of IL-6, appears dispensable for Eμ-myc driven lymphomagenesis. We conclude that the growth-promoting and anti-apoptotic mechanisms activated by IL-6 are critically involved in Eμ-myc driven tumor initiation and progression, but the B cell intrinsic expression of STAT3 is not required.
2021-02-02 | GSE165205 | GEO
Project description:The inflammatory cytokine IL-6 is known to play a causal role in the promotion of cancer, although the underlying mechanisms remain to be completely understood. Interplay between endogenous and environmental cues determines the fate of cancer development. The Eμ-myc transgenic mouse expresses elevated levels of c-Myc in the B cell lineage and develops B cell lymphomas with associated mutations in p53 or other genes linked to apoptosis. We generated Eμ-myc mice that either lacked the IL-6 gene, or lacked the STAT3 gene specifically in B cells to determine the role of the IL-6/JAK/STAT3 pathway in tumor development. Using the Eμ-myc lymphoma mouse model, we demonstrate that IL-6 is a critical tumor promoter during early stages of B cell lymphomagenesis. IL-6 is shown to inhibit the expression of tumor suppressors, notably BIM and PTEN, and this may contribute to advancing MYC-driven B cell tumorigenesis. Several miRNAs known to target BIM and PTEN are upregulated by IL-6 and likely lead to the stable suppression of pro-apoptotic pathways early during the tumorigenic process. STAT3, a classical downstream effector of IL-6, appears dispensable for Eμ-myc driven lymphomagenesis. We conclude that the growth-promoting and anti-apoptotic mechanisms activated by IL-6 are critically involved in Eμ-myc driven tumor initiation and progression, but the B cell intrinsic expression of STAT3 is not required.
| S-EPMC7924759 | biostudies-literature
Project description:Pcgf6 suppresses Myc-induced lymphomagenesis
| PRJNA785557 | ENA
Project description:Max is an obligate dimerization partner for the Myc transcription factors and for several repressors, such as Mnt, Mxd1-4 and Mga, collectively thought to antagonize Myc function in transcription and oncogenesis. Mga, in particular, is part of the variant Polycomb group repressive complex PRC1.6. Here, we show that ablation of the distinct PRC1.6 subunit Pcgf6 – but not Mga – accelerates Myc-induced lymphomagenesis in Eµ-myc transgenic mice. Unexpectedly, however, Pcgf6 loss shows no significant impact on transcriptional profiles, in neither pre-tumoral B-cells, nor lymphomas. Altogether, these data unravel an unforeseen, Mga- and PRC1.6-independent tumor suppressor activity of Pcgf6.
2021-12-05 | GSE189999 | GEO
Project description:Max is an obligate dimerization partner for the Myc transcription factors and for several repressors, such as Mnt, Mxd1-4 and Mga, collectively thought to antagonize Myc function in transcription and oncogenesis. Mga, in particular, is part of the variant Polycomb group repressive complex PRC1.6. Here, we show that ablation of the distinct PRC1.6 subunit Pcgf6 – but not Mga – accelerates Myc-induced lymphomagenesis in Eµ-myc transgenic mice. Unexpectedly, however, Pcgf6 loss shows no significant impact on transcriptional profiles, in neither pre-tumoral B-cells, nor lymphomas. Altogether, these data unravel an unforeseen, Mga- and PRC1.6-independent tumor suppressor activity of Pcgf6.
2021-12-05 | GSE189989 | GEO
Project description:This study examines the transcriptional changes invoked by activation of gp130 signaling in different mouse models of B cell lymphomagenesis. In order to study the in vivo effects of aberrant activity of IL-6/IL-6R/gp130-JAK/STAT3 signaling, we designed a transgene that allows conditional expression of L-gp130 by generating a ROSA26 knock-in mouse strain where compound L-gp130 and ZsGreen expression from the CAG promoter is prevented by a loxP- and a rox-flanked stop cassette. Total RNA extracted from purified B cells from young CD19Cre+/- ;L-gp130fl/+ and wildtype control mice was sequenced using unique molecular identifiers (UMI) in a paired end design where read1 corresponds to the cDNA and read2 contains the UMI. Furthermore, aging CD19Cre+/- ;L-gp130fl/+ animals developed tumors located predominantly in mesenteric lymph nodes. Infiltration of CD19;L-gp activated B cells was determined by Flow Cytometry and ZsGreen expression. Total RNA from tumors generally containing >60% ZsGreen+ cells was profiled as described above, for tumors with lower CD19;L-gp activated B cell content FACS was applied. In order to study the effects of activated IL-6/IL-6R/gp130-JAK/STAT3 signaling on Eµ-Myc-driven lymphomagenesis, CD19Cre;L-gp130fl;Eµ-Myc triple transgenic mice were generated and fetal liver hematopoietic stem/progenitor cell (FL-HSPC) grafts were transplanted into lethally irradiated syngeneic mice alongside FL-HSPC from CD19Cre;L-gp130f and Eµ-Myc control mice. Lastly, IL-6/IL-6R/gp130-JAK/STAT3 signaling was activated in the entire hematopoetic system using Vav1Cre resulting in Vav1Cre+/- ;L-gp130fl/+ animals. Independent of the time point of activation during hematopoietic and B cell differentiation, all Cre;L-gp compound mice succumbed to tumors of B cell origin.
2019-06-06 | GSE132148 | GEO
Project description:Pcgf6 suppresses Myc-induced lymphomagenesis [RNA-seq]
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Project description:Pcgf6 suppresses Myc-induced lymphomagenesis [ChIP-seq]
| PRJNA785540 | ENA
Project description:Interleukin-21 (IL-21) is a type 1 cytokine essential for immune cell differentiation and function. Although IL-21 can activate several STAT family transcription factors, previous studies focused mainly on the role of STAT3 in IL-21 signaling. Here, we investigated the role of STAT1 and show that STAT1 and STAT3 have at least partially opposing roles in IL-21 signaling in CD4+ T cells. IL-21 induced STAT1 phosphorylation, and this was augmented in Stat3-deficient CD4+ T cells. RNA-Seq analysis of CD4+ T cells from Stat1- and Stat3-deficient mice revealed that both STAT1 and STAT3 are critical for IL-21-mediated gene regulation. Expression of some genes, including Tbx21 and Ifng, was differentially regulated by STAT1 and STAT3, and interestingly, ChIP-Seq analysis showed that STAT3 binding at Tbx21 and Ifng loci was attenuated in Stat1-deficient cells. Moreover, opposing actions of STAT1 and STAT3 on IFN- expression in CD4+ T cells were demonstrated in vivo during chronic lymphocytic choriomeningitis (LCMV) infection. Finally, IL-21-mediated induction of STAT1 phosphorylation, as well as IFNG and TBX21 expression, were higher in CD4+ T cells from patients with autosomal dominant hyper-IgE syndrome (AD-HIES), which is caused by STAT3 deficiency. These data indicate an interplay between STAT1 and STAT3 in fine-tuning IL-21 actions. Genome-wide transcription factors mapping and binding of STAT3 in mouse CD4+ T cells in both WT and Stat1-deficient mice. RNA-Seq is performed in mouse CD4+ T cells in WT, Stat1-deficient and Stat3-deficient mice.
2015-07-01 | E-GEOD-63204 | biostudies-arrayexpress
Project description:Over-expressed MYC binds to virtually all active promoters within a cell, although with different binding affinities, and modulates gene expression, both positively and negatively. Here, we show that during lymphomagenesis in Eµ-myc transgenic mice, MYC directly up-regulates the transcription of the core snRNP assembly genes, including PRMT5, an arginine methyltransferase, that methylates Sm proteins as an early step in lymphomagenesis. This coordinated regulatory effect is direct and is critical for snRNP biogenesis, the maintenance of effective mRNA splicing and cellular viability in cycling cells, in either fibroblasts or B-cells. mRNA profiles of wild type and pre-tumoral eu-myc mice by deep sequencing, in triplicate, using Illumina NextSeq 500
2015-05-19 | E-GEOD-60188 | biostudies-arrayexpress