scholarly journals Stat3 co-operates with mutant Ezh2Y641F to regulate gene expression and limit the anti-tumor immune response in melanoma

2021 ◽  
Author(s):  
Sarah Zimmerman ◽  
Samantha J Nixon ◽  
Leela Raj ◽  
Pei Yu Chen ◽  
Sofia Smith ◽  
...  
Keyword(s):  
Gene Expression ◽  
Immune Response ◽  
Transcriptional Repression ◽  
Point Mutations ◽  
Disease Recurrence ◽  
Genetic Alterations ◽  
Genetically Engineered ◽  
Polycomb Repressive Complex 2 ◽  
Genetically Engineered Mouse Models

One of the most frequently genetically altered chromatin modifiers in melanoma is the Enhancer of Zeste Homolog 2 (EZH2), the catalytic component of the Polycomb Repressive Complex 2 (PRC2), which methylates lysine 27 on histone 3 (H3K27me3), a chromatin mark associated with transcriptional repression. Genetic alterations in EZH2 in melanoma include amplifications and activating point mutations at tyrosine 641 (Y641). The oncogenic role of EZH2 in melanoma has previously been determined; however, its downstream oncogenic mechanisms remain underexplored. Here, we found that in genetically engineered mouse models, expression of Ezh2Y641F causes up-regulation of a subset of interferon-regulated genes in melanoma cells, suggesting a potential role of the immune system in the pathogenesis of these mutations. Expression of these interferon genes was not a result of changes in H3K27me3, but through a direct and non-canonical interaction between Ezh2 and Signal Transducer And Activator of Transcription 3 (Stat3). We found that Ezh2 directly binds Stat3, and that in the presence of Ezh2Y641F mutant, Stat3 protein is hypermethylated. Expression of Stat3 was required to maintain an anti-tumor immune response and its depletion resulted in faster melanoma progression and disease recurrence. Molecularly, Stat3 and Ezh2 bind together at many genomic loci, and, in association with the rest of the PRC2 complex, repress gene expression. These results suggest that one of the oncogenic mechanisms of Ezh2-mediated melanomagenesis is through evasion of the anti-tumor immune response, and that the immunomodulatory properties of Stat3 are context dependent.

scholarly journals A Joint Odyssey into Cancer Genetics

2019 ◽  
Vol 3 (1) ◽  
pp. 1-19 ◽  
Author(s):  
Suzanne Cory ◽  
Jerry M. Adams
Keyword(s):  
Gene Expression ◽  
Cell Death ◽  
Anticancer Agents ◽  
Molecular Basis ◽  
Cancer Genetics ◽  
Genetically Engineered ◽  
Genetically Engineered Mouse Models ◽  
Chromosome Translocations ◽  
The Earth

The war on cancer that began some 40 years ago with the discovery of oncogenes is starting to be won. We feel fortunate to have contributed to several advances. Here we recall how molecular biology became our scientific passion, how we met from opposite ends of the earth, and how our 50-year odyssey has taken us from gene expression through immunogenetics to exploring the molecular basis of cancer and cell death. We describe the scientific discoveries that motivated us and remarkable scientists who influenced us. We sketch our studies that clarified the role of chromosome translocations in cancer and established the value of genetically engineered mouse models of tumorigenesis. Finally, we outline how our findings with many talented close colleagues on cell death regulation stimulated the development of remarkable new anticancer agents called BH3 mimetics, which are encouraging hope that many more malignancies will become controllable and even curable.

Molecular defects in thyroid carcinomas: Role of the RET oncogene in thyroid neoplastic transformation

1995 ◽  
Vol 133 (5) ◽  
pp. 513-522 ◽  
Author(s):  
Massimo Santoro ◽  
Michele Grieco ◽  
Rosa Marina Melillo ◽  
Alfredo Fusco ◽  
Giancarlo Vecchio
Keyword(s):  
Tyrosine Kinases ◽  
Point Mutations ◽  
Neoplastic Transformation ◽  
Thyroid Neoplasms ◽  
Genetic Alterations ◽  
Thyroid Carcinomas ◽  
Molecular Defects ◽  
Genetic And Environmental Factors ◽  
Definition Of

Santoro M, Grieco M, Melillo RM, Fusco A, Vecchio G. Molecular defects in thyroid carcinomas. Role of the RET oncogene in thyroid neoplastic transformation. Eur J Endocrinol 1995;133:513–22. ISSN 0804–4643 Tumors are believed to arise as a result of an accumulation of mutations in critical genes involved in the control of cell proliferation. Thyroid neoplasms represent a good model for studying the role of these mutations in epithelial cell multistep carcinogenesis because they comprise a broad spectrum of lesions with different degrees of malignancy. Recent reports have described the involvement of specific genetic alterations in different types of thyroid neoplasms. Papillary carcinomas are characterized by the activation of the receptor tyrosine kinases RET and TRK-A proto-oncogenes. Ras point mutations are frequently observed in tumors with follicular histology and a high prevalence of p53 point mutations have been found in anaplastic carcinomas. A definition of molecular defects characterizing thyroid tumors will be helpful in establishing sensitive and specific detection strategies and, in addition, to define genetic and environmental factors important for their pathogenesis. Giancarlo Vecchio, Dipartimento di Biologia e Patologia Cellulare e Molecolare "L, Califano", Facoltà di Medicina e Chirurgia, Università degli Studi di Napoli "Federico II", via S Pansini 5, 80131 Napoli, Italy

scholarly journals FBXO11-Mediated Proteolysis of BAHD1 Relieves PRC2-dependent Transcriptional Repression in Erythropoiesis

Blood ◽  
2020 ◽  
Author(s):  
Peng Xu ◽  
Daniel C. Scott ◽  
Beisi Xu ◽  
Yu Yao ◽  
Ruopeng Feng ◽  
...  
Keyword(s):  
Gene Expression ◽  
Ubiquitin Ligase ◽  
Transcriptional Repression ◽  
E3 Ubiquitin Ligase ◽  
Histone Mark ◽  
Developmentally Delayed ◽  
Hematopoietic Development ◽  
Polycomb Repressive Complex 2 ◽  
Stem And Progenitor Cells ◽  
Erythroid Maturation

The histone mark H3K27me3 and its reader/writer Polycomb repressive complex 2 (PRC2) mediate widespread transcriptional repression in stem and progenitor cells. Mechanisms that regulate this activity are critical for hematopoietic development but poorly understood. Here we show that the E3 ubiquitin ligase FBXO11 relieves PRC2-mediated repression during erythroid maturation by targeting its newly identified substrate BAHD1, an H3K27me3 reader that recruits transcriptional co-repressors. Erythroblasts lacking FBXO11 are developmentally delayed, with reduced expression of maturation-associated genes, most of which harbor bivalent histone marks (activating H3K4me3 and repressive H3K27me3), bind BAHD1, and fail to recruit the erythroid transcription factor GATA1. The BAHD1 complex interacts physically with PRC2 and depletion of either component restores FBXO11-deficient erythroid gene expression. Our studies identify BAHD1 as a novel effector of PRC2-mediated repression and reveal how a single E3 ubiquitin ligase eliminates PRC2 repression at developmentally poised bivalent genes during erythropoiesis.

Neuropathology of Mowat–Wilson Syndrome

2020 ◽  
Vol 23 (4) ◽  
pp. 322-325
Author(s):  
Miriam R. Conces ◽  
Anna Hughes ◽  
Christopher R. Pierson
Keyword(s):  
Mouse Models ◽  
Hirschsprung Disease ◽  
Genetically Engineered ◽  
Facial Dysmorphism ◽  
Genetically Engineered Mouse Models ◽  
Brain Malformations ◽  
Neuroimaging Data ◽  
The Brain ◽  
Correlate Data

Mowat–Wilson syndrome (MWS) is a syndromic form of Hirschsprung disease that is characterized by variable degrees of intellectual disability, characteristic facial dysmorphism, and a diverse set of other congenital malformations due to haploinsufficiency of ZEB2. A variety of brain malformations have been described in neuroimaging studies of MWS patients, and the role of ZEB2 in the brain has been studied in a multitude of genetically engineered mouse models that are now available. However, a paucity of autopsy information limits our ability to correlate data from neuroimaging studies and animal models with actual MWS patient tissues. Here, we report the autopsy neuropathology of a 19-year-old male patient with MWS. Autopsy neuropathology findings correlated well with the reported MWS neuroimaging data and are in keeping with data from genetically engineered MWS mouse models. This autopsy enhances our understanding of ZEB2 function in human brain development and demonstrates the reliability of MWS murine models.

Association of phosphatidylinositol 3-kinase (PI3K) pathway activation with increased immune checkpoint expression in colorectal cancer (CRC) patients.

2018 ◽  
Vol 36 (4_suppl) ◽  
pp. 653-653 ◽  
Author(s):  
Maliha Nusrat ◽  
Jason Roszik ◽  
Riham Katkhuda ◽  
David Menter ◽  
Kanwal Pratap Singh Raghav ◽  
...  
Keyword(s):  
Gene Expression ◽  
Immune Response ◽  
Protein Expression ◽  
Immune Cell ◽  
Early Stage ◽  
Pi3k Pathway ◽  
Genetic Alterations ◽  
Immune Checkpoints ◽  
Pik3ca Mutations ◽  
The Impact

653 Background: PI3K pathway is a known modulator of anti-tumor immune response and is frequently activated in CRC through genetic alterations such as PTEN loss (PTENloss) and PIK3CA mutations (PIK3CAmut). This study aims to determine the impact of these alterations on immune cell infiltration, priming and activation in early stage CRC patients (pts). Methods: Immune infiltrates and checkpoints were evaluated using quantitative immunohistochemistry (IHC) on primary CRC (N = 59) for both center of tumor (CT) and invasive margin (IM). Pts were evaluated by presence or absence of either PTENloss or PIK3CAmut (collectively termed PI3K pathway alterations). Microsatellite unstable (MSI) and stable (MSS) tumors were analyzed separately. Clinicopathologic data was examined for potential associations with PI3K pathway alterations. Separately, mRNA data (Agilent) was obtained for immune related genes from an internal cohort with PTEN and PIK3CA annotation (N = 73). Results: 59 pts comprised IHC cohort (40 MSS, 19 MSI); 23 pts (39%) had PTENloss or PIK3CAmut. In Agilent cohort, 16 of 73 pts (22%) had PI3K pathway alterations. In MSS CRC, these alterations were more common in CMS1 (p = 0.03), on right side (p = 0.048) and with peritumoral lymphocytes (p = 0.031). MSS pts with PI3K pathway alterations had higher PD1 protein expression (p = 0.04), 2.1 and 2.3 times increased density of CD3+ (p = 0.01) and CD8+ (p = 0.04) cells respectively, and higher Granzyme B protein expression (p = 0.04) in the CT. These pts also had higher PDL1 gene expression (p = 0.046). MSS CRC pts with PIK3CAmut similarly had 2 times more PDL1 protein expression in epithelial cells of the IM (p = 0.01). Alternate checkpoints were also increased in pts with PI3K pathway alterations, including higher protein expression of LAG3 in CT (P = 0.046) and higher gene expression of CTLA4, TIM3, and TIGIT (P < 0.05 for all). Conclusions: PI3K pathway activated MSS CRC is associated with increased immune engagement, but also upregulation of key immune checkpoints in early stage tumors resulting in an ineffective immune response. Combination of PI3K pathway inhibition with immunotherapy merits investigation in this subset of pts.

Differentiation of the Gastric Mucosa II. Role of gastrin in gastric epithelial cell proliferation and maturation

2006 ◽  
Vol 291 (5) ◽  
pp. G762-G765 ◽  
Author(s):  
Renu N. Jain ◽  
Linda C. Samuelson
Keyword(s):  
Genetically Engineered ◽  
Gastric Epithelial Cells ◽  
Balanced Growth ◽  
Cellular Targets ◽  
Genetically Engineered Mouse Models ◽  
Gastric Physiology ◽  
Ecl Cell ◽  
Acid Secreting ◽  
And Function

Gastrin is the principal hormonal inducer of gastric acid secretion. The cellular targets for gastrin in the stomach are the acid-secreting parietal cell and histamine-producing enterochromaffin-like (ECL) cell. Gastrin is also a growth factor, with hypergastrinemia resulting in increased proliferation of gastric progenitor cells and a thickened mucosa. This review presents insights into gastrin function revealed by genetically engineered mouse models, demonstrating a new role for gastrin in the maturation of parietal and ECL cells. Thus, gastrin regulates many aspects of gastric physiology, with tight regulation of gastrin levels required to maintain balanced growth and function of gastric epithelial cells.

scholarly journals Sox2 is an oncogenic driver of small cell lung cancer

2019 ◽  
Author(s):  
Ellen Voigt ◽  
Hannah Wollenzien ◽  
Josh Feiner ◽  
Ethan Thompson ◽  
Madeline Vande Kamp ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Genetic Alterations ◽  
Small Cell ◽  
Genetically Engineered ◽  
Small Cell Lung ◽  
Genetically Engineered Mouse Models ◽  
Oncogenic Driver ◽  
New Treatments

AbstractAlthough many cancer prognoses have improved in the past fifty years due to advancements in treatments, there has been little to no improvement in therapies for small cell lung cancer (SCLC) which currently has a five-year survival rate of less than 7%. One promising avenue to improve treatment for SCLC is to understand its underlying genetic alterations that drive its formation and growth. One such mutation in SCLC, which appears in many cancers, is of the Rb gene. When mutated, Rb causes hyperproliferation and loss of cellular identity. Normally Rb promotes differentiation by regulating lineage specific transcription factors including regulation of pluripotency factors such as Sox2. However, there is evidence that when certain tissues lose Rb, Sox2 becomes upregulated and promotes oncogenesis. To better understand the relationship between Rb and Sox2 and to uncover new treatments for SCLC we have studied the role of Sox2 in Rb loss initiated tumors by investigating both the tumor initiation in SCLC genetically engineered mouse models, as well as tumor maintenance in SCLC cell lines.

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