scholarly journals Gene Expression and Mutational Profile in BAP-1 Inactivated Melanocytic Lesions of Progressive Malignancy from a Patient with Multiple Lesions

Genes ◽  
2021 ◽  
Vol 13 (1) ◽  
pp. 10
Author(s):  
Yan Zhou ◽  
Andrew C. Nelson ◽  
Yuyu He ◽  
Sarah A. Munro ◽  
Kyu Young Song ◽  
...  
Keyword(s):  
Gene Expression ◽  
Transcription Factors ◽  
Gene Expression Analysis ◽  
Mapk Pathway ◽  
Familial Cancer ◽  
Receptor Protein ◽  
Cancer Predisposition Syndrome ◽  
Molecular Features ◽  
Melanocytic Lesions ◽  
Clinical Interest

BAP-1 (BRCA1-associated protein 1) inactivated melanocytic lesions are a group of familial or sporadic lesions with unique histology and molecular features. They are of great clinical interest, at least in part due to the potential for malignant transformation and association with a familial cancer predisposition syndrome. Here, we describe a patient with multiple spatially and temporally distinct melanocytic lesions with loss of BAP1 expression by immunohistochemistry. RNA sequencing was performed on three independent lesions spanning the morphologic spectrum: a benign nevus, an atypical tumor, and a melanoma arising from a pre-existing BAP1-inactivated nevus. The three lesions demonstrated largely distinct gene expression and mutational profiles. Gene expression analysis revealed that genes involved in receptor protein kinase pathways were progressively upregulated from nevus to melanoma. Moreover, a clear enrichment of genes regulated in response to UV radiation was found in the melanoma from this patient, as well as upregulation of MAPK pathway-related genes and several transcription factors related to melanomagenesis.

scholarly journals PS1 - 169 Discovering the Treatment Refractory BTIC Population in Group 3 Medulloblastoma through Therapy Adapted Patient-Derived Human Mouse Xenograft (PDX) Model

2016 ◽  
Vol 43 (S4) ◽  
pp. S10-S10
Author(s):  
D. Bakhshinyan ◽  
T. Vijayakumar ◽  
B. Manoranjan ◽  
N. McFarlane ◽  
C. Venugopal ◽  
...  
Keyword(s):  
Gene Expression ◽  
Expression Analysis ◽  
Gene Expression Analysis ◽  
High Rate ◽  
Multiple Time ◽  
Self Renewal ◽  
Molecular Features ◽  
Post Radiation ◽  
Group 3 ◽  
Treatment Refractory

Medulloblastoma (MB), the most common malignant pediatric brain tumor, is categorized into four molecular subgroups. Given the high rate of metastatic dissemination at diagnosis and recurrence in Group 3 MBs, these patients have the worst clinical outcome with a 5-year survivorship of approximately 50%. By adapting the existing COG (Children’s Oncology Group) Protocol for children with newly diagnosed high-risk MB, for treatment of immuno-deficient mice intracranially engrafted with human MB brain tumour initiating cells we aim to identify and characterize the treatment-refractory cell population in Group 3 MBs. Mice were sacrificed at multiple time points during the course of tumor development and therapy: (i) at engraftment; (ii) post-radiation; (iii) post-radiation and chemotherapy; and (iv) at MB recurrence. MB cell populations recovered separately from brains and spines were comprehensively profiled for gene expression analysis, stem cell and molecular features to generate a global, comparative profile of MB cells through therapy. We report a higher expression of CD133, Sox2 and Bmi1 in addition to increased self-renewal capacity following chemoradiotherapy treatment. The enrichment map constructed from global gene expression analysis showed an increase in pathways regulating self-renewal, DNA repair and chemoresistance post-therapy despite the apparent decrease in tumour size and vascularity. Additionally, from gene expression at MB recurrence, we identified a list of genes that negatively correlate with survival in patients diagnosed with Group 3 MB. A differential genomic profile of the “treatment-responsive” tumors against those that fail therapy may contribute to discovery of novel therapeutic approaches for the most aggressive subgroup of MB.

Control of the expression of inflammatory response genes

2003 ◽  
Vol 70 ◽  
pp. 95-106 ◽  
Author(s):  
Jeremy Saklatvala ◽  
Jonathan Dean ◽  
Andrew Clark
Keyword(s):  
Gene Expression ◽  
Transcription Factors ◽  
Inflammatory Response ◽  
Mapk Pathway ◽  
Interleukin 1 ◽  
Mitogen Activated Protein Kinase ◽  
Mrna Levels ◽  
Matrix Metalloproteinase 1 ◽  
Inflammatory Stimuli ◽  
Mitogen Activated Protein

The expression of genes involved in the inflammatory response is controlled both transcriptionally and post-transcriptionally. Primary inflammatory stimuli, such as microbial products and the cytokines interleukin-1 (IL-1) and tumour necrosis factor α (TNFα), act through receptors of either the Toll and IL-1 receptor (TIR) family or the TNF receptor family. These cause changes in gene expression by activating four major intracellular signalling pathways that are cascades of protein kinases: namely the three mitogen-activated protein kinase (MAPK) pathways, and the pathway leading to activation of the transcription factor nuclear factor ϰB (NFϰB). The pathways directly activate and induce the expression of a limited set of transcription factors which promote the transcription of inflammatory response genes. Many of the mRNAs are unstable, and are stabilized by the p38 MAPK pathway. Instability is mediated by clusters of the AUUUA motif in the 3″ untranslated regions of the mRNAs. Control of mRNA stability provides a means of increasing the amplitude of a response and allows rapid adjustment of mRNA levels. Not all mRNAs stabilized by p38 contain AUUUA clusters; for example, matrix metalloproteinase-1 and -3 mRNAs lack these clusters, but are stabilized. Inflammatory gene expression is inhibited by glucocorticoids. These suppress MAPK signalling by inducing a MAPK phosphatase. This may be a significant mechanism additional to that by which the glucocorticoid receptor interferes with transcription factors.

Single Cell Level Genome-Wide Gene Expression Analysis of Bone Marrow-Derived Oct-4+ very Small Embryonic-Like Stem Cells (VSELs) Revealed That a Polycomb Group Protein Ezh2 Regulates VSELs Pluripotency by Maintaining Bivalent Domains At Promoters of Important Homeodomain-Containing Developmental Transcription Factors

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 2345-2345
Author(s):  
Magda Kucia ◽  
Rui Liu ◽  
Kasia Mierzejewska ◽  
Wan Wu ◽  
Janina Ratajczak ◽  
...  
Keyword(s):  
Gene Expression ◽  
Stem Cells ◽  
Transcription Factors ◽  
Single Cell ◽  
Gene Expression Analysis ◽  
Polycomb Group ◽  
Polycomb Group Protein ◽  
Genome Wide ◽  
Group Protein ◽  
Genome Wide Gene Expression

Abstract Abstract 2345 Recently, we identified a population of very small embryonic-like (VSEL) stem cells (SCs) in adult bone marrow (BM) (Leukemia 2006:20;857). These Oct4+CXCR4+SSEA-1+Sca-1+CD45−Lin− VSELs are capable of differentiation in vitro into cells from all three germ lineages and in in vivo animal models they can be specified into mesenchymal stem cells (MSCs) (Stem Cells Dev 2010:19;1557), cardiomyocytes (Stem Cell 2008:26;1646), and long-term engrafting hematopoietic stem cells (HSCs) (Exp Hematol 2011:39;225). Be employing gene-expression and epigenetic profiling studies we reported that VSELs in BM have germ-line stem cell like epigenetic features including i) open/active chromatin structure in Oct4 promoter, ii) parent-of-origin specific reprogramming of genomic imprinting (Leukemia 2009, 23, 2042–2051), and iii) that they share several markers with epiblast-derived primordial germ cells (PGCs), in particular with migratory PGCs (Leukemia 2010, 24, 1450–1461). However, it was not clear how VSELs maintain pluripotent state. To address this issue we recently employed single cell-based genome-wide gene expression analysis and found that, Oct4+ VSELs i) express a similar, yet nonidentical, transcriptome as embryonic stem-cells (ESCs), ii) up-regulate cell-cycle checkpoint genes, and iii) down-regulate genes involved in protein turnover and mitogenic pathways. Interestingly, our single cell library studies also revelaed that Ezh2, a polycomb group protein, is highly expressed in VSELs. This protein is well known to be involved in maintaining a bivalent domains (BDs) at promoters of important homeodomain-containing developmental transcription factors. Of note a presence of BDs is characteristic for pluripotent stem cells (e.g., ESCs) and as result of Ezh2 overexpression, VSELs, like ESCs, exhibit BDs - bivalently modified nucleosomes (trimethylated H3K27 and H3K4) at promoters of important homeodomain-containing developmental transcription factors (Sox21 Nkx2.2 Dlx1 Zfpm2 Irx2 Lbx1h Hlxb9 Pax5 HoxA3). Of note, spontaneous (as seen during differentiation) or RNA interference-enforced down-regulation of Ezh2 removes BDs what, results in lose of their plurioptentiality and de-repression of several BD-regulated genes that control their tissue commitment. In conclusion, Our results show for first time that in addition to the expression of pluripotency core transcription factor Oct-4, VSELs, like other pluripotent stem-cells, maintain their pluripotent state through an Ezh2-dependent BD-mediated epigenetic mechanism. Based on this our genome-wide gene expression study not only advances our understanding of biological processes that govern VSELs pluripotency, differentiation, and quiescence but will also help to develop better protocols for ex vivo expansion of these promising cells for potential application in regenerative medicine. Disclosures: Ratajczak: Neostem Inc: Consultancy, Research Funding.

scholarly journals ALK-Negative Anaplastic Large Cell Lymphomas Encompass Distinct Subgroups Including an ALK-Positive-like Subgroup with Favorable Prognosis

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 2403-2403
Author(s):  
Kwok Him Rex Au Yeung ◽  
Veronica Russell ◽  
William Choi ◽  
Alice Wong ◽  
Lawrence Tsui ◽  
...  
Keyword(s):  
Gene Expression ◽  
T Cell ◽  
Research Funding ◽  
Gene Expression Analysis ◽  
Cell Lymphoma ◽  
Large Cell ◽  
Genetic Alterations ◽  
The Other ◽  
Molecular Features ◽  
Alk Positive

Abstract Introduction ALK-negative anaplastic large cell lymphoma (ALK- ALCL) is an uncommon type of T-cell non-Hodgkin lymphoma (T-NHL) with worse prognosis compared to ALK-positive (ALK+) ALCLs. Most published studies on the genomics of T-NHL have focused on peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS), and previous studies of ALCL described rearrangements in DUSP22 and TP63 and mutations in genes comprising the JAK/STAT pathway as common genetic drivers in ALK- ALCL. The degree to which these drivers affect survival or other molecular features of ALK- ALCL remains unknown. Here, we describe novel subgroups of ALK- ALCL that exhibit distinct survival. One subgroup appears molecularly similar to ALK+ALCLs and is associated with favorable survival while the second subgroup is quite distinct from ALK- ALCLs and associated with poor outcomes. Methods and Results Eighty-two ALK- ALCL patients were recruited to the Atlas of Blood Cancer (ABC) genomes project, a worldwide consortium established to define the molecular origins of blood cancers. Tumor biopsies from these patients, as well as 10 ALK+ ALCL samples for comparison were obtained from participating institutions. Each case was subjected to centralized pathology review by an experienced panel of hematopathologists to ensure the accuracy of the diagnosis. All cases, along with paired normal tissues, were subjected to DNA and RNA (whole exome-level) sequencing on the Illumina platform to identify mutations and expression changes for each of these cases using methods well established in our group and described previously. We first examined the genetic alterations in ALK- ALCLs. In addition to frequently described genetic alterations such as TP63 and DUSP22 rearrangements, as well as mutations in JAK1, STAT3 and TP53, we also detected mutations in ERBB4, SETD2 and KMT2D, which may serve as potential novel drivers and have not been described previously to our knowledge. We next performed comparative gene expression analysis of the ALK- and ALK+ ALCLs. Surprisingly, a proportion of ALK- ALCL cases (38%) clustered together with ALK+ ALCLs and had a signature resembling ALK+ cases, which we designated as "ALK-like ALCL" here. Both the ALK-like ALCLs and the other ALK- ALCL cases showed decreased ALK expression compared to the ALK+ ALCLs by gene expression analysis. These results point to downstream pathways that are common among ALK+ALCLs and ALK-like ALCLs, but different from the other ALK- ALCLs. Gene set enrichment analysis revealed that the ALK-like ALCLs overexpressed genes in pathways related to monocyte and fibroblast activation, whereas the remaining ALK- ALCLs overexpressed genes in the T follicular helper cells, memory T cells and adaptive immune response-related pathways (P<0.001 in all cases). Kaplan-Meier survival analysis revealed that patients with ALK-like ALCL had significantly better overall survival compared to the other cases (P=0.01, Wald test). Conclusion Our data indicate that ALK- ALCLs represent a heterogeneous group of diseases and comprise at least two distinct subgroups that can be identified based on their similarity to the ALK+ ALCLs. The ALK-like ALCLs demonstrated distinct molecular features and favorable outcomes. Our results provide a potentially new approach to patient risk-stratification and pathological classification of this disease. Disclosures Kwong: Celgene: Consultancy, Honoraria, Research Funding; Bayer: Consultancy, Honoraria, Research Funding; Astellas: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Bristol Myers Squibb: Consultancy, Honoraria, Research Funding; BeiGene: Consultancy, Honoraria, Research Funding; Gilead: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Merck: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Roche: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding. Jaye: Stemline Therapeutics: Honoraria. Behdad: Roche/Foundation Medicine: Speakers Bureau; Thermo Fisher: Speakers Bureau; Lilly: Speakers Bureau. Hsi: AbbVie Inc, Eli Lilly: Research Funding. Dave: Data Driven Bioscience: Current equity holder in publicly-traded company.

scholarly journals cAMP Receptor Protein ControlsVibrio choleraeGene Expression in Response to Host Colonization

mBio ◽  
2018 ◽  
Vol 9 (4) ◽  
Author(s):  
Jainaba Manneh-Roussel ◽  
James R. J. Haycocks ◽  
Andrés Magán ◽  
Nicolas Perez-Soto ◽  
Kerstin Voelz ◽  
...  
Keyword(s):  
Gene Expression ◽  
Transcription Factors ◽  
Vibrio Cholerae ◽  
Expression Patterns ◽  
Lifestyle Changes ◽  
Receptor Protein ◽  
Camp Receptor Protein ◽  
Host Colonization ◽  
Content Type ◽  
Camp Receptor

ABSTRACTThe bacteriumVibrio choleraeis native to aquatic environments and can switch lifestyles to cause disease in humans. Lifestyle switching requires modulation of genetic systems for quorum sensing, intestinal colonization, and toxin production. Much of this regulation occurs at the level of gene expression and is controlled by transcription factors. In this work, we have mapped the binding of cAMP receptor protein (CRP) and RNA polymerase across theV. choleraegenome. We show that CRP is an integral component of the regulatory network that controls lifestyle switching. Focusing on a locus necessary for toxin transport, we demonstrate CRP-dependent regulation of gene expression in response to host colonization. Examination of further CRP-targeted genes reveals that this behavior is commonplace. Hence, CRP is a key regulator of manyV. choleraegenes in response to lifestyle changes.IMPORTANCECholera is an infectious disease that is caused by the bacteriumVibrio cholerae. Best known for causing disease in humans, the bacterium is most commonly found in aquatic ecosystems. Hence, humans acquire cholera following ingestion of food or water contaminated withV. cholerae. Transition between an aquatic environment and a human host triggers a lifestyle switch that involves reprogramming ofV. choleraegene expression patterns. This process is controlled by a network of transcription factors. In this paper, we show that the cAMP receptor protein (CRP) is a key regulator ofV. choleraegene expression in response to lifestyle changes.

scholarly journals A Full-length Transcriptome and Gene Expression Analysis Reveal Genes and Molecular Elements Expressed During Seed Development in Gnetum Luofuense

2020 ◽  
Author(s):  
Nan deng ◽  
Chen Hou ◽  
Boxiang He ◽  
Fengfeng Ma ◽  
Qingan Song ◽  
...  
Keyword(s):  
Gene Expression ◽  
Transcription Factors ◽  
Gene Expression Analysis ◽  
Molecular Mechanisms ◽  
Immature Stage ◽  
Full Length ◽  
Differentially Expressed ◽  
Mature Stage ◽  
Medicinal Uses ◽  
A Site

Abstract Background: Gnetum is an economically important tropical and subtropical gymnosperm genus with various dietary, industrial and medicinal uses. Many carbohydrates, proteins and secondary metabolic compounds accumulate during the ripening of Gnetum seeds.However, the molecular mechanisms related to this process remain unknown. Results: We therefore assembled a full-length transcriptome from immature and mature G. luofuenseseeds using PacBio sequencingreads. We identified a total of 5,726 novel genes, 9,061 alternative splicing events, 3,551 lncRNAs, 2,160 transcription factors, and 359 fusion genes, and we found that 8,512 genes possessed at least one poly(A) site. In addition, gene expression comparisons of six transcriptomes generated by Illumina sequencing showed that14,323 genes were differentially expressed from an immature stage to a mature stage with 7,891 genes upregulated and 6,432 genes downregulated. The expression of 14 differentially expressed transcription factors from the MADS-box, Aux/IAA and bHLH families was validated by qRT-PCR, suggesting that they may have important roles in seed ripening of G. luofuense. Conclusions:These findings provide a valuable molecular resource for domestication and cultivation of Gnetum species.

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