scholarly journals Two Distinct Classes of Thymic Tumors in Patients with MEN1 Show LOH at the MEN1 Locus

2021 ◽  
Author(s):  
Adel Mandl ◽  
James M Welch ◽  
Gayathri Kapoor ◽  
Vaishali I Parekh ◽  
David S Schrump ◽  
...  
Keyword(s):  
Tumor Development ◽  
Suppressor Gene ◽  
Endocrine Tumors ◽  
Loss Of Function ◽  
Wild Type ◽  
Thymic Tumor ◽  
Molecular Events ◽  
Associated Tumors ◽  
Thymic Tumors

Patients with the multiple endocrine neoplasia type 1 (MEN1) syndrome carry germline heterozygous loss-of-function mutations in the MEN1 gene which predisposes them to the development of various endocrine and non-endocrine tumors. Over 90% of these tumors have been shown to undergo biallelic inactivation of the MEN1 tumor suppressor gene by somatic loss of the wild-type allele resulting in loss of heterozygosity (LOH) at chromosome 11q13, the MEN1 gene locus. An uncommon manifestation of MEN1 is thymic neuroendocrine tumor (thymic NET), also referred to as thymic carcinoid, which in MEN1 patients is a major cause of mortality. In contrast to the other frequent NETs in MEN1 patients (pancreas, parathyroid, pituitary), LOH at the MEN1 locus has not been demonstrated in MEN1-associated thymic tumors. Therefore, it is generally thought that thymic tumor development in MEN1 patients is dependent on other somatic molecular events rather than a second hit to the MEN1 gene and its pathogenesis is largely unknown. The lack of knowledge of its pathogenesis limits the ability to explore therapies directed at this tumor, which is the most aggressive of all MEN1-associated tumors. The goal of this study was to investigate the molecular events contributing to thymic tumor development in our well-characterized cohort of MEN1 patients by evaluating LOH at the MEN1 locus and by utilizing transcriptomics to identify possible molecular hits that may lead to tumor development and could be considered for targeted therapy.

scholarly journals MEN4 and CDKN1B mutations: the latest of the MEN syndromes

2017 ◽  
Vol 24 (10) ◽  
pp. T195-T208 ◽  
Author(s):  
Rami Alrezk ◽  
Fady Hannah-Shmouni ◽  
Constantine A Stratakis
Keyword(s):  
Tumor Suppressor ◽  
Neuroendocrine Tumors ◽  
Pituitary Adenomas ◽  
Wide Spectrum ◽  
Susceptibility Gene ◽  
Germline Mutations ◽  
Suppressor Gene ◽  
Loss Of Function ◽  
Putative Tumor Suppressor

Multiple endocrine neoplasia (MEN) refers to a group of autosomal dominant disorders with generally high penetrance that lead to the development of a wide spectrum of endocrine and non-endocrine manifestations. The most frequent among these conditions is MEN type 1 (MEN1), which is caused by germline heterozygous loss-of-function mutations in the tumor suppressor geneMEN1. MEN1 is characterized by primary hyperparathyroidism (PHPT) and functional or nonfunctional pancreatic neuroendocrine tumors and pituitary adenomas. Approximately 10% of patients with familial or sporadic MEN1-like phenotype do not haveMEN1mutations or deletions. A novel MEN syndrome was discovered, initially in rats (MENX), and later in humans (MEN4), which is caused by germline mutations in the putative tumor suppressorCDKN1B. The most common phenotype of the 19 established cases of MEN4 that have been described to date is PHPT followed by pituitary adenomas. Recently, somatic or germline mutations inCDKN1Bwere also identified in patients with sporadic PHPT, small intestinal neuroendocrine tumors, lymphoma and breast cancer, demonstrating a novel role forCDKN1Bas a tumor susceptibility gene for other neoplasms. In this review, we report on the genetic characterization and clinical features of MEN4.

scholarly journals Host Adhesive Activities and Virulence of Novel Fimbrial Proteins of Porphyromonas gingivalis

2009 ◽  
Vol 77 (8) ◽  
pp. 3294-3301 ◽  
Author(s):  
Deanne L. Pierce ◽  
So-ichiro Nishiyama ◽  
Shuang Liang ◽  
Min Wang ◽  
Martha Triantafilou ◽  
...  
Keyword(s):  
Porphyromonas Gingivalis ◽  
Matrix Proteins ◽  
Loss Of Function ◽  
Wild Type ◽  
Host Proteins ◽  
Cxc Chemokine Receptor 4 ◽  
Functional Complex ◽  
Chemokine Receptor 4

ABSTRACT The fimbriae of Porphyromonas gingivalis mediate critical roles in host colonization and evasion of innate defenses and comprise polymerized fimbrilin (FimA) associated with quantitatively minor accessory proteins (FimCDE) of unknown function. We now show that P. gingivalis fimbriae lacking FimCDE fail to interact with the CXC-chemokine receptor 4 (CXCR4), and bacteria expressing FimCDE-deficient fimbriae cannot exploit CXCR4 in vivo for promoting their persistence, as the wild-type organism does. Consistent with these loss-of-function experiments, purified FimC and FimD (but not FimE) were shown to interact with CXCR4. However, significantly stronger binding was observed when a combination of all three proteins was allowed to interact with CXCR4. In addition, FimC and FimD bound to fibronectin and type 1 collagen, whereas FimE failed to interact with these matrix proteins. These data and the fact that FimE is required for the association of FimCDE with P. gingivalis fimbriae suggest that FimE may recruit FimC and FimD into a functional complex, rather than directly binding host proteins. Consistent with this notion, FimE was shown to bind both FimC and FimD. In summary, the FimCDE components cooperate and impart critical adhesive and virulence properties to P. gingivalis fimbriae.

scholarly journals Involvement of the MEN1 gene locus in familial isolated hyperparathyroidism

2002 ◽  
pp. 313-322 ◽  
Author(s):  
A Villablanca ◽  
WS Wassif ◽  
T Smith ◽  
A Hoog ◽  
O Vierimaa ◽  
...  
Keyword(s):  
Multiple Endocrine Neoplasia Type ◽  
Suppressor Gene ◽  
Tumour Suppressor Gene ◽  
Comparative Genomic Hybridisation ◽  
Comparative Genomic ◽  
Wild Type ◽  
Chromosome 11 ◽  
Men1 Gene ◽  
Parathyroid Disease

BACKGROUND: Familial isolated hyperparathyroidism (FIHP) is a hereditary disorder characterised by uni- or multiglandular parathyroid disease. A subset of families are likely to be genetic variants of other familial tumour syndromes in which PHPT is the main feature, for example multiple endocrine neoplasia type 1 (MEN 1) and the hyperparathyroidism-jaw tumour syndrome (HPT-JT). OBJECTIVE: To investigate seven families diagnosed with FIHP, each with two to eight affected family members, to clarify the underlying genetic mechanism. METHODS: The entire MEN1 gene was sequenced for germline mutations and, in addition, tumour specimens were analysed in comparative genomic hybridisation and loss of heterozygosity studies. RESULTS: Two families exhibited MEN1 mutations, L112V and 1658delG, which were associated with loss of the wild-type 11q13 alleles in all tumours analysed. In the remaining five families, no MEN1 mutation was identified. CONCLUSION: These results support the involvement of the MEN1 tumour suppressor gene in the pathogenesis of some of the FIHP kindreds. However, loss on chromosome 11 was seen in all tumours exhibiting somatic deletions, although in two families the tumour deletions involved 11q distal to MEN1. We conclude that the altered MEN1 gene function is of importance in the development of FIHP.

scholarly journals Non-Coding RNA and Tumor Development in Neurofibromatosis Type 1: ANRIL Rs2151280 Is Associated with Optic Glioma Development and a Mild Phenotype in Neurofibromatosis Type 1 Patients

Genes ◽  
2019 ◽  
Vol 10 (11) ◽  
pp. 892 ◽  
Author(s):  
Viviana Tritto ◽  
Luca Ferrari ◽  
Silvia Esposito ◽  
Paola Zuccotti ◽  
Donatella Bianchessi ◽  
...  
Keyword(s):  
Neurofibromatosis Type 1 ◽  
Tumor Development ◽  
Neurofibromatosis Type ◽  
Regulatory Function ◽  
Circular Rnas ◽  
Optic Glioma ◽  
Mild Phenotype ◽  
Peripheral Nerve Sheath Tumors ◽  
Associated Tumors

Non-coding RNAs (ncRNAs) are known to regulate gene expression at the transcriptional and post-transcriptional levels, chromatin remodeling, and signal transduction. The identification of different species of ncRNAs, microRNAs (miRNAs), circular RNAs (circRNAs), and long ncRNAs (lncRNAs)—and in some cases, their combined regulatory function on specific target genes—may help to elucidate their role in biological processes. NcRNAs’ deregulation has an impact on the impairment of physiological programs, driving cells in cancer development. We here carried out a review of literature concerning the implication of ncRNAs on tumor development in neurofibromatosis type 1 (NF1), an inherited tumor predisposition syndrome. A number of miRNAs and a lncRNA has been implicated in NF1-associated tumors, such as malignant peripheral nerve sheath tumors (MPNSTs) and astrocytoma, as well as in the pathognomonic neurofibromas. Some authors reported that the lncRNA ANRIL was deregulated in the blood of NF1 patients with plexiform neurofibromas (PNFs), even if its role should be further elucidated. We here provided original data concerning the association of a specific genotype about ANRIL rs2151280 with the presence of optic gliomas and a mild expression of the NF1 phenotype. We also detected the LOH of ANRIL in different tumors from NF1 patients, supporting the involvement of ANRIL in some NF1-associated tumors. Our results suggest that ANRIL rs2151280 may be a potential diagnostic and prognostic marker, addressing early diagnosis of optic glioma and predicting the phenotype severity in NF1 patients.

scholarly journals Menin Missense Mutants Associated with Multiple Endocrine Neoplasia Type 1 Are Rapidly Degraded via the Ubiquitin-Proteasome Pathway

2004 ◽  
Vol 24 (15) ◽  
pp. 6569-6580 ◽  
Author(s):  
Hiroko Yaguchi ◽  
Naganari Ohkura ◽  
Maho Takahashi ◽  
Yuko Nagamura ◽  
Issay Kitabayashi ◽  
...  
Keyword(s):  
Multiple Endocrine Neoplasia ◽  
Multiple Endocrine Neoplasia Type ◽  
Suppressor Gene ◽  
Missense Mutations ◽  
Wild Type ◽  
Ubiquitin Proteasome Pathway ◽  
Endocrine Neoplasia ◽  
Ubiquitin Proteasome ◽  
Proteasome Pathway

ABSTRACT MEN1 is a tumor suppressor gene that is responsible for multiple endocrine neoplasia type 1 (MEN1) and that encodes a 610-amino-acid protein, called menin. While the majority of germ line mutations identified in MEN1 patients are frameshift and nonsense mutations resulting in truncation of the menin protein, various missense mutations have been identified whose effects on menin activity are unclear. For this study, we analyzed a series of menin proteins with single amino acid alterations and found that all of the MEN1-causing missense mutations tested led to greatly diminished levels of the affected proteins in comparison with wild-type and benign polymorphic menin protein levels. We demonstrate here that the reduced levels of the mutant proteins are due to rapid degradation via the ubiquitin-proteasome pathway. Furthermore, the mutants, but not wild-type menin, interact both with the molecular chaperone Hsp70 and with the Hsp70-associated ubiquitin ligase CHIP, and the overexpression of CHIP promotes the ubiquitination of the menin mutants in vivo. These findings reveal that MEN1-causing missense mutations lead to a loss of function of menin due to enhanced proteolytic degradation, which may be a common mechanism for inactivating tumor suppressor gene products in familial cancer.

scholarly journals Disruption of the ARF transcriptional activator DMP1 facilitates cell immortalization, Ras transformation, and tumorigenesis

2000 ◽  
Vol 14 (14) ◽  
pp. 1797-1809 ◽  
Author(s):  
Kazushi Inoue ◽  
Renren Wen ◽  
Jerold E. Rehg ◽  
Masashi Adachi ◽  
John L. Cleveland ◽  
...  
Keyword(s):  
Cell Lines ◽  
Interleukin 2 ◽  
Embryonic Stem ◽  
Suppressor Gene ◽  
Null Mouse ◽  
Dependent Manner ◽  
Loss Of Function ◽  
Wild Type ◽  
Functional Protein ◽  
Early Passage

The DMP1 transcription factor induces the ARF tumor suppressor gene in mouse fibroblasts, leading to cell cycle arrest in a p53-dependent manner. We disrupted sequences encoding the DNA-binding domain of DMP1 in mouse embryonic stem cells and derived animals lacking the functional protein. DMP1-null animals are small at birth, and males develop more slowly than their wild-type littermates. Some adult animals exhibit seizures and/or obstuctive uropathy, each of unknown cause. The growth of explantedDMP1-null mouse embryo fibroblasts (MEFs) is progressively retarded as cells are passaged in culture on defined transfer protocols; but, unlike the behavior of normal cells, p19ARF, Mdm2, and p53 levels remain relatively low and DMP1-null MEFs do not senesce. Whereas the establishment of cell lines from MEFs is usually always accompanied by either p53 or ARF loss of function, continuously passaged DMP1-null cells readily give rise to established 3T3 and 3T9 cell lines that retain wild-type ARFand functional p53 genes. Early-passage DMP1-null cells, like MEFs from either ARF-null or p53-null mice, can be morphologically transformed by oncogenic Ha-Ras (Val-12) alone. Splenic lymphocytes harvested from both DMP1-null andARF-null mice exhibit enhanced proliferative responses in long-term cultures when stimulated to divide with antibody to CD3 and interleukin-2. Although only 1 of 40 DMP1-null animals spontaneously developed a tumor in the first year of life, neonatal treatment with dimethylbenzanthracene or ionizing radiation induced tumors of various histologic types that were not observed in similarly treated DMP1+/+ animals. Karyotypic analyses of MEFs and lymphomas from DMP1-null animals revealed pseudodiploid chromosome numbers, consistent with the retention of wild-type p53. Together, these data suggest that ARF function is compromised, but not eliminated, in animals lacking functional DMP1.

scholarly journals Haploinsufficiency of p18INK4c Sensitizes Mice to Carcinogen-Induced Tumorigenesis

2003 ◽  
Vol 23 (4) ◽  
pp. 1269-1277 ◽  
Author(s):  
Feng Bai ◽  
Xin-Hai Pei ◽  
Virginia L. Godfrey ◽  
Yue Xiong
Keyword(s):  
Wide Spectrum ◽  
Tumor Development ◽  
Pituitary Tumors ◽  
Cdk Inhibitors ◽  
Cyclin D ◽  
Wild Type Allele ◽  
Cyclin Dependent Kinase ◽  
Loss Of Function ◽  
Wild Type ◽  
Targeted Deletion

ABSTRACT The INK4 family of cyclin-dependent kinase (CDK) inhibitors negatively regulates cyclin D-dependent CDK4 and CDK6 and thereby retains the growth-suppressive function of Rb family proteins. Mutations in the CDK4 gene conferring INK4 resistance are associated with familial and sporadic melanoma in humans and result in a wide spectrum of tumors in mice. Whereas loss of function of other INK4 genes in mice leads to little or no tumor development, targeted deletion of p18 INK4c causes spontaneous pituitary tumors and lymphoma late in life. Here we show that treatment of p18 null and heterozygous mice with a chemical carcinogen resulted in tumor development at an accelerated rate. The remaining wild-type allele of p18 was neither mutated nor silenced in tumors derived from heterozygotes. Hence, p18 is a haploinsufficient tumor suppressor in mice.

scholarly journals Activated IL-6 signaling contributes to the pathogenesis of, and is a novel therapeutic target for, CALR-mutated MPNs

2021 ◽  
Vol 5 (8) ◽  
pp. 2184-2195
Author(s):  
Manjola Balliu ◽  
Laura Calabresi ◽  
Niccolò Bartalucci ◽  
Simone Romagnoli ◽  
Laura Maggi ◽  
...  
Keyword(s):  
Messenger Rna ◽  
Therapeutic Potential ◽  
Myeloproliferative Neoplasms ◽  
Supporting Cell ◽  
Loss Of Function ◽  
Wild Type ◽  
Colony Forming Unit ◽  
Thrombopoietin Receptor ◽  
Cd34 Cells

Abstract Calreticulin (CALR), an endoplasmic reticulum–associated chaperone, is frequently mutated in myeloproliferative neoplasms (MPNs). Mutated CALR promotes downstream JAK2/STAT5 signaling through interaction with, and activation of, the thrombopoietin receptor (MPL). Here, we provide evidence of a novel mechanism contributing to CALR-mutated MPNs, represented by abnormal activation of the interleukin 6 (IL-6)-signaling pathway. We found that UT7 and UT7/mpl cells, engineered by clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9) to express the CALR type 1–like (DEL) mutation, acquired cytokine independence and were primed to the megakaryocyte (Mk) lineage. Levels of IL-6 messenger RNA (mRNA), extracellular-released IL-6, membrane-associated glycoprotein 130 (gp130), and IL-6 receptor (IL-6R), phosphorylated JAK1 and STAT3 (p-JAK1 and p-STAT3), and IL-6 promoter region occupancy by STAT3 all resulted in increased CALR DEL cells in the absence of MPL stimulation. Wild-type, but not mutated, CALR physically interacted with gp130 and IL-6R, downregulating their expression on the cell membrane. Agents targeting gp130 (SC-144), IL-6R (tocilizumab [TCZ]), and cell-released IL-6 reduced proliferation of CALR DEL as well as CALR knockout cells, supporting a mutated CALR loss-of-function model. CD34+ cells from CALR-mutated patients showed increased levels of IL-6 mRNA and p-STAT3, and colony-forming unit–Mk growth was inhibited by either SC144 or TCZ, as well as an IL-6 antibody, supporting cell-autonomous activation of the IL-6 pathway. Targeting IL-6 signaling also reduced colony formation by CD34+ cells of JAK2V617F-mutated patients. The combination of TCZ and ruxolitinib was synergistic at very low nanomolar concentrations. Overall, our results suggest that target inhibition of IL-6 signaling may have therapeutic potential in CALR, and possibly JAK2V617F, mutated MPNs.

scholarly journals Hematopoietic cells from mice deficient in wild-type p53 are more resistant to induction of apoptosis by some agents

Blood ◽  
1993 ◽  
Vol 82 (4) ◽  
pp. 1092-1096 ◽  
Author(s):  
J Lotem ◽  
L Sachs
Keyword(s):  
Cell Death ◽  
Tumor Development ◽  
Hematopoietic Cells ◽  
Suppressor Gene ◽  
Wild Type ◽  
Myeloid Progenitor Cells ◽  
Induction Of Apoptosis ◽  
Wild Type P53 ◽  
Macrophage Colony ◽  
Deficient Mice

Wild-type p53 is a tumor-suppressor gene that can induce cell death by apoptosis when expressed in myeloid leukemic and some other types of tumor cells. However, the question remained as to what extent wild-type p53 is a mediator of apoptosis in normal cells. We have used mice deficient in wild-type p53 to determine whether induction of apoptosis in hematopoietic cells from these p53 deficient mice is defective. We show here that bone marrow myeloid progenitor cells from p53-deficient mice are more resistant to induction of apoptosis when there was only a low concentration of the viability factors granulocyte-macrophage colony-stimulating factor; interleukins-1 alpha, -3, and -6; or stem cell factor; or when apoptosis was induced in these cells by irradiation or heat shock. The loss of one allele of wild-type p53 was sufficient for increased resistance. The higher resistance to apoptosis in p53-deficient mice was also found in irradiated thymocytes, but not in thymocytes treated with dexamethasone or in mature peritoneal granulocytes. The degree of resistance in irradiated myeloid progenitors and thymocytes showed a dosage effect of the number of wild- type p53 genes. The results show that wild-type p53 is involved in the induction of apoptosis by some agents in normal hematopoietic cells. Loss of wild-type p53 can, therefore, contribute to tumor development by decreasing cell death at low concentrations of viability factors and after exposure to a DNA-damaging agent. The results also show that there are wild-type p53-dependent and -independent pathways of normal cell apoptosis.

scholarly journals Suppression-Replacement KCNQ1 Gene Therapy for Type 1 Long QT Syndrome

Circulation ◽  
2021 ◽  
Author(s):  
Steven M. Dotzler ◽  
C.S. John Kim ◽  
William A.C. Gendron ◽  
Wei Zhou ◽  
Dan Ye ◽  
...  
Keyword(s):  
Gene Therapy ◽  
Long Qt Syndrome ◽  
Delayed Rectifier ◽  
Loss Of Function ◽  
Wild Type ◽  
Long Qt ◽  
Α Subunit ◽  
Cardiac Model ◽  
Qt Syndrome

Background: Type 1 long QT syndrome (LQT1) is caused by loss-of-function variants in the KCNQ1 -encoded K v 7.1 potassium channel α-subunit which is essential for cardiac repolarization, providing the slow delayed rectifier current (IKs). No current therapies target the molecular cause of LQT1. Methods: A dual-component "suppression-and-replacement" (SupRep) KCNQ1 gene therapy was created by cloning a KCNQ1 shRNA and a "shRNA-immune" (shIMM) KCNQ1 cDNA modified with silent variants in the shRNA target site, into a single construct. The ability of KCNQ1-SupRep gene therapy to suppress and replace LQT1-causative variants in KCNQ1 was evaluated via heterologous expression in TSA201 cells. For a human in vitro cardiac model, induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) were generated from four patients with LQT1 (KCNQ1-Y171X, -V254M, -I567S, and -A344A/spl) and an unrelated healthy control. CRISPR-Cas9 corrected isogenic control iPSC-CMs were made for two LQT1 lines (correction of KCNQ1-V254M and KCNQ1-A344A/spl). FluoVolt voltage dye was used to measure the cardiac action potential duration (APD) in iPSC-CMs treated with KCNQ1-SupRep. Results: In TSA201 cells, KCNQ1-SupRep achieved mutation-independent suppression of wild-type KCNQ1 and three LQT1-causative variants (KCNQ1-Y171X, -V254M, and -I567S) with simultaneous replacement of KCNQ1-shIMM as measured by allele-specific qRT-PCR and western blot. Using FluoVolt voltage dye to measure the cardiac APD in the four LQT1 patient-derived iPSC-CMs, treatment with KCNQ1-SupRep resulted in shortening of the pathologically prolonged APD at both 90% (APD 90 ) and 50% (APD 50 ) repolarization resulting in APD values similar to those of the two isogenic controls. Conclusions: This study provides the first proof-of-principle gene therapy for complete correction of LQTS. As a dual-component gene therapy vector, KCNQ1-SupRep successfully suppressed and replaced KCNQ1 to normal wild-type levels. In TSA201 cells, co-transfection of LQT1-causative variants and KCNQ1-SupRep caused mutation-independent suppression-and-replacement of KCNQ1 . In LQT1 iPSC-CMs, KCNQ1-SupRep gene therapy shortened the APD, thereby eliminating the pathognomonic feature of LQT1.

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