COX-2/PGE2 upregulation contributes to the chromosome 17p-deleted lymphoma
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ABSTRACT:
PROVIDER: PRJNA613637 | ENA |
REPOSITORIES: ENA
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Project description:Chromosome 17p deletions are one of the most frequent chromosomal alterations in human cancers and also lymphoma. Although it has been assumed to be equal to p53 loss for a long time, there are emerging evidence suggesting that there would be additional p53–independent mechanisms. Our previous work identified ALOX15B, an arachidonate lipoxygenase, as a 17p tumor suppressor in lymphoma. Interestingly, five of the six ALOX genes locate on this region and frequently co-deleted with TP53. Among them, ALOX15B, ALOX12B and ALOXE3 are adjacent to one another and proximal to the centromere relative to TP53, while ALOX12 and ALOX15 are distal to the centromere relative to TP53. Herein, we show that each of the five 17p ALOX genes repress Myc-driven lymphomagenesis in mice. Mechanistically, deficiency of the ALOX arachidonate metabolism pathway activates the paralleling COX-PGE2 pathway, resulting in increasing PTGS2 expression and PGE2 level. PGE2 prevents apoptosis of pre-B cells and Ptgs2 knockdown extends the latency of Myc;shAlox15b lymphoma in vivo. Further, shAlox15b lymphoma cells are more sensitive to COX-2 inhibitor celecoxib than control lymphoma cells. Importantly, the ALOX-COX metabolism unbalance is also observed in human cancers with del(17p). Taken together, our studies reveal the tumor suppression functions of all of the five ALOX genes on chromosome 17p in lymphoma and an unprecedented arachidonate metabolism unbalance between the ALOX and COX pathways underlying human cancers with 17p deletions.
2022-12-21 | GSE147264 | GEO
Project description:Distinct genetic abnormalities such as TP53 deletion at 17p13.1, have been identified as having an adverse prognostic relevance in B-cell chronic lymphocytic leukemia (B-CLL). Conventional cytogenetic studies have shown that TP53 deletion in B-CLL is associated predominantly with 17p loss resulting from complex chromosomal rearrangements. We performed genome-wide DNA (SNPs arrays), fluorescence in situ hybridization (FISH) and gene expression profiling (GEP) analyses to investigate the significance of 17p loss in a panel of 71 genetically well-characterized B-CLLs in Binet stage A, 18 of which carried a TP53 monoallelic deletion. Combined SNP arrays and FISH approaches showed 17p loss in all of the TP53-deleted cases, with breakpoints scattered along the 17p11.2 region. Mutations in exons 5 to 9 of TP53 were found in 9/12 deleted samples. GEP of 60 B-CLLs, including 7 patients with 17p loss, identified 40 differentially expressed genes in 17p- versus 17p normal samples, 35 of which were down-regulated in 17p- tumors. The majority (30/35) of these transcripts, including putative tumor suppressor genes, mapped to 17p. Overall, these data indicate that, beside TP53 deletion, the concomitant loss of 17p arm may contribute to the strong negative prognostic impact known to be associated with this lesion in B-CLL. This SuperSeries is composed of the SubSeries listed below.
2008-11-11 | GSE11038 | GEO
Project description:Distinct genetic abnormalities such as TP53 deletion at 17p13.1, have been identified as having an adverse prognostic relevance in B-cell chronic lymphocytic leukemia (B-CLL). Conventional cytogenetic studies have shown that TP53 deletion in B-CLL is associated predominantly with 17p loss resulting from complex chromosomal rearrangements. We performed genome-wide DNA (SNPs arrays), fluorescence in situ hybridization (FISH) and gene expression profiling (GEP) analyses to investigate the significance of 17p loss in a panel of 71 genetically well-characterized B-CLLs in Binet stage A, 18 of which carried a TP53 monoallelic deletion. Combined SNP arrays and FISH approaches showed 17p loss in all of the TP53-deleted cases, with breakpoints scattered along the 17p11.2 region. Mutations in exons 5 to 9 of TP53 were found in 9/12 deleted samples. GEP of 60 B-CLLs, including 7 patients with 17p loss, identified 40 differentially expressed genes in 17p- versus 17p normal samples, 35 of which were down-regulated in 17p- tumors. The majority (30/35) of these transcripts, including putative tumor suppressor genes, mapped to 17p. Overall, these data indicate that, beside TP53 deletion, the concomitant loss of 17p arm may contribute to the strong negative prognostic impact known to be associated with this lesion in B-CLL. Keywords: genomic analysis of B-CLL with 17p loss patients
2008-11-11 | GSE11036 | GEO
Project description:Distinct genetic abnormalities such as TP53 deletion at 17p13.1, have been identified as having an adverse prognostic relevance in B-cell chronic lymphocytic leukemia (B-CLL). Conventional cytogenetic studies have shown that TP53 deletion in B-CLL is associated predominantly with 17p loss resulting from complex chromosomal rearrangements. We performed genome-wide DNA (SNPs arrays), fluorescence in situ hybridization (FISH) and gene expression profiling (GEP) analyses to investigate the significance of 17p loss in a panel of 71 genetically well-characterized B-CLLs in Binet stage A, 18 of which carried a TP53 monoallelic deletion. Combined SNP arrays and FISH approaches showed 17p loss in all of the TP53-deleted cases, with breakpoints scattered along the 17p11.2 region. Mutations in exons 5 to 9 of TP53 were found in 9/12 deleted samples. GEP of 60 B-CLLs, including 7 patients with 17p loss, identified 40 differentially expressed genes in 17p- versus 17p normal samples, 35 of which were down-regulated in 17p- tumors. The majority (30/35) of these transcripts, including putative tumor suppressor genes, mapped to 17p. Overall, these data indicate that, beside TP53 deletion, the concomitant loss of 17p arm may contribute to the strong negative prognostic impact known to be associated with this lesion in B-CLL. Keywords: transcriptional analysis of B-CLL with 17p loss patients
2008-11-11 | GSE9992 | GEO
Project description:Distinct genetic abnormalities such as TP53 deletion at 17p13.1, have been identified as having an adverse prognostic relevance in B-cell chronic lymphocytic leukemia (B-CLL). Conventional cytogenetic studies have shown that TP53 deletion in B-CLL is associated predominantly with 17p loss resulting from complex chromosomal rearrangements. We performed genome-wide DNA (SNPs arrays), fluorescence in situ hybridization (FISH) and gene expression profiling (GEP) analyses to investigate the significance of 17p loss in a panel of 71 genetically well-characterized B-CLLs in Binet stage A, 18 of which carried a TP53 monoallelic deletion. Combined SNP arrays and FISH approaches showed 17p loss in all of the TP53-deleted cases, with breakpoints scattered along the 17p11.2 region. Mutations in exons 5 to 9 of TP53 were found in 9/12 deleted samples. GEP of 60 B-CLLs, including 7 patients with 17p loss, identified 40 differentially expressed genes in 17p- versus 17p normal samples, 35 of which were down-regulated in 17p- tumors. The majority (30/35) of these transcripts, including putative tumor suppressor genes, mapped to 17p. Overall, these data indicate that, beside TP53 deletion, the concomitant loss of 17p arm may contribute to the strong negative prognostic impact known to be associated with this lesion in B-CLL. This SuperSeries is composed of the following subset Series: GSE9992: Molecular and transcriptional characterization of chromosome 17p loss in chronic lymphocytic leukemia, experiment A GSE11036: Molecular and transcriptional characterization of chromosome 17p loss in chronic lymphocytic leukemia, experiment B Keywords: SuperSeries Refer to individual Series
2008-11-11 | E-GEOD-11038 | biostudies-arrayexpress
Project description:We performed whole genome profiling in order to determine the landscape of genetic alterations assoicated with a subset of CLL that is characterized by deletions in 17p The number of copy number alterations predicted shorter time to treatment among patients untreated at sampling. Chromosome 3p, 4p, and 9p were frequently deleted in del(17p) CLL and strongly associated with shorter OS. We conclude that del(17p) has a unique genomic profile characterized typically by TP53 mutation with novel CNAs and novel drivers, with increasing genomic complexity of any type associated with worse overall survival.
2016-10-21 | GSE74239 | GEO
Project description:Chromosome copy number variations are a hallmark of human cancers and among them chromosome 17p loss is the most common one and associated with poor prognosis. Our previous work demonstrates that 17p deletions can promote tumorigenesis more than p53 loss. Herein, with multiple functional genetic strategies, we identify a new 17p tumor suppressor, PHD finger protein 23 (PHF23). PHF23 deficiency impaires B cell differentiation and promotes Myc-driven lymphoma. Mechanistically, PHF23, a H3K4me3 reader, directly binds and represses the deacetylation activity of the SIN3-HDAC complex through its N-terminus, which coordinates two major active histone markers H3K4me3 and H3K27ac for activation of downstream B cell-differentiation genes and tumor suppressors. Further, we show that dysregulation of the PHF23-SIN3-HDAC complex is essential for PHF23 deficiency-induced tumorigenesis and maintenance. Hence, our study reveals a novel epigenetic regulatory mechanism that contributed to the pathology of 17p deleted cancers and suggests novel susceptibility of this miserable disease.
2020-12-20 | GSE145190 | GEO
Project description:To comprehensively understand how dendritic cells (DCs) are reprogrammed by lung fibroblasts- and their derived COX-2/PGE2, we employed lung fibroblasts isolated from WT or Ptgs2-/- mice, and collect their conditioned medium (CM) to stimulate the ex vivo cultured bone marrow (BM)-derived DCs (BM-DCs), with the PGE2 treatment as a control. After the treatment, BM-DCs were harvested for RNA extraction and the transcriptional profiles were analyzed by RNA sequencing (RNA-seq).
2022-07-19 | E-MTAB-11873 | biostudies-arrayexpress
Project description:Prostaglandin E2 (PGE2) is involved in several inflammatory conditions including periodontitis. The aim of this study was to investigate the global gene expression profile of tumor necrosis factor alpha (TNFalpha) stimulated human gingival fibroblasts, focusing on signal pathways related to PGE2 production and the new PGE2-synthesizing enzymes, prostaglandin E synthases (PGES). The expression of microsomal prostaglandin E synthase-1 (mPGES-1) as well as the upstream cyclooxygenase-2 (COX-2) was up-regulated by TNFalpha, accompanied by increased PGE2 production. In contrast, the expression of microsomal prostaglandin E synthase-2 (mPGES-2) and cytosolic prostaglandin E synthase (cPGES) was unaffected by TNFalpha. Using microarray analysis in a time-course factorial design including time points 1, 3 and 6 h, we identified differentially expressed genes in response to TNFalpha treatment. Enrichment analysis of microarray data identified two positively regulated signal transduction pathways: c-Jun N-terminal kinase (JNK) and Nuclear Factor-kappaB (NF-kappaB). We used specific inhibitors and phosphorylation analysis to confirm their role in PGE2 regulation. Both JNK and NF-kappaB inhibitors reduced the TNFalpha-stimulated up-regulation of mPGES-1 and COX-2 as well as subsequent PGE2 production. The novel finding that TNFalpha-stimulated mPGES-1 is regulated by JNK suggests this kinase as a potential future target for treatment strategies in inflammatory disorders, including periodontitis. Keywords: Time course, gene expression, factorial design.
2008-12-11 | GSE13903 | GEO
Project description:We compared the effects of mPGES-1 inhibitor Compound III (CIII) with the cyclooxygenase (COX)-2 inhibitor NS-398 on protein and lipid profiles in interleukin (IL)-1β induced A549 lung cancer cells using mass spectrometry. Inhibition of mPGES-1 decreased PGE2 production and increased PGF2α and thromboxane B2 (TXB2) formation, while inhibition of COX-2 decreased the production of all three prostanoids. Our proteomics results revealed that CIII downregulated multiple canonical pathways including eIF2, eIF4/P70S6K, and mTOR signaling, compared to NS-398 that activated these pathways.
2019-05-20 | PXD013490 | Pride