C-Myc misregulation triggers complex process of genomic instability

Genetic stability is an essential factor for the cellular integrity. Failure in its maintenance leads to accumulation of errors derived from the process of DNA replication, cellular metabolism, action of endogenous and exogenous DNA damaging factors and eventually, as a final outcome tumor initiation and progression occur. Overall manifestation of c-Myc deregulation in many tumors and different mechanisms of Myc?s action toward genomic stability suggest that this gene plays a central role in destabilization of genome. Microarray studies and functional genomics approach led us to conclusion that c-Myc can control nuclear architecture in global fashion since about 15% of all cellular genes are regulated by this transcription factor. Deregulation of c-Myc gene triggers a composite network of genomic instability that may result in several different outcomes as: locus-specific amplification, formation of extrachromosomal elements (EEs), chromosomal instability, long-range illegitimate recombination, point mutations, DNA breakage and nuclear structure reorganization. This review outlines the growing evidence that c-Myc oncogene induces a complex network of genomic instability and describes systems and circumstances under which deregulation of c-Myc results in specific types of genomic alteration.

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SANTA-SIM: simulating viral sequence evolution dynamics under selection and recombination

Virus Evolution ◽

10.1093/ve/vez003 ◽

2019 ◽

Vol 5 (1) ◽

Cited By ~ 5

Author(s):

Abbas Jariani ◽

Christopher Warth ◽

Koen Deforche ◽

Pieter Libin ◽

Alexei J Drummond ◽

...

Keyword(s):

Software Package ◽

Point Mutations ◽

Sequence Evolution ◽

Biological Processes ◽

Viral Sequence ◽

Recombination Point ◽

Wide Range ◽

Cross Platform ◽

Evolution Dynamics ◽

Inference Methods

Abstract Simulations are widely used to provide expectations and predictive distributions under known conditions against which to compare empirical data. Such simulations are also invaluable for testing and comparing the behaviour and power of inference methods. We describe SANTA-SIM, a software package to simulate the evolution of a population of gene sequences forwards through time. It models the underlying biological processes as discrete components: replication, recombination, point mutations, insertion–deletions, and selection under various fitness models and population size dynamics. The software is designed to be intuitive to work with for a wide range of users and executable in a cross-platform manner.

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Follicular lymphoma with t(8;14)(q24;q32): a distinct clinical and molecular subset of t(8;14)-bearing lymphomas

Blood ◽

10.1182/blood.v79.8.2124.2124 ◽

1992 ◽

Vol 79 (8) ◽

pp. 2124-2130 ◽

Cited By ~ 18

Author(s):

M Ladanyi ◽

K Offit ◽

NZ Parsa ◽

MR Condon ◽

N Chekka ◽

...

Keyword(s):

Follicular Lymphoma ◽

Point Mutations ◽

Consecutive Series ◽

Target Area ◽

Intron 1 ◽

Exon 1 ◽

Myc Gene ◽

Hodgkin's Lymphomas ◽

Ig Heavy Chain ◽

Histologic Subtypes

Abstract The presence of the translocation t(8;14)(q24;q32) has not been well described in follicular lymphoma (FL). In a consecutive series of 278 karyotypically abnormal non-Hodgkin's lymphomas (NHL), six patients with FL showing a t(8;14) without a t(14;18)(q32;q21) were identified. They ranged in age from 45 to 73 years. The cell type was mixed in four patients, small-cleaved in one, and large-cleaved in one; four cases also contained diffuse areas. All cases tested displayed monoclonal surface Ig. The clinical courses were consistent with the histologic subtypes, being less aggressive than other t(8;14)-bearing NHL. In five cases, frozen tissue was available for Southern blotting. The BCL2 gene showed a germline configuration when studied with the MBR, MCR, and 5′ cDNA probes. The MYC gene also appeared unrearranged using an exon-1 probe with EcoRI or HindIII digestion. Analysis of the Ig heavy chain (IgH) gene with a JH region probe and BamHI or EcoRI digestion showed only one rearranged band in all cases, indicating that the 14q32 breakpoint did not lie in either the J or switch-mu (SM) regions. In four cases, the exon-1/intron-1 border of the MYC gene, a target area for point mutations in cases of t(8;14) that do not display rearrangements of the MYC gene, was enzymatically amplified and sequenced; no point mutations were identified. The indolent behavior of our six cases, and the finding that the molecular structure of the t(8;14) in these cases does not follow the pattern of breakpoint sites and point mutations defined in other histologic subtypes of NHL with this translocation, suggest that the t(8;14) in these cases is cytogenetically and molecularly distinct from the t(8;14) seen in high- grade NHLs, and is relatively ineffectual in terms of MYC deregulation, or that other genetic elements at these chromosomal sites may be involved. Further analysis of these tumors may provide insights into MYC deregulation and BCL2-independent FL.

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Induction of clonal monocyte-macrophage tumors in vivo by a mouse c-myc retrovirus: rearrangement of the CSF-1 gene as a secondary transforming event.

Molecular and Cellular Biology ◽

10.1128/mcb.7.2.664 ◽

1987 ◽

Vol 7 (2) ◽

pp. 664-671 ◽

Cited By ~ 27

Author(s):

W R Baumbach ◽

E R Stanley ◽

M D Cole

Keyword(s):

Tumor Cells ◽

Gene Rearrangement ◽

Tumor Formation ◽

Dna Rearrangement ◽

Phagocytic Cells ◽

Proviral Integration ◽

Myc Oncogene ◽

Myc Gene ◽

Stimulating Factor

A mouse retrovirus containing the c-myc oncogene was found to induce tumors of mononuclear phagocytic cells in vivo. All tumors expressed the c-myc retroviral gene but not the endogenous c-myc gene (with one exception), and virtually all tumors were clonal with a unique proviral integration. This observation, coupled with a lag time in tumor formation, suggests that a second event, in addition to c-myc proviral integration, is necessary for the generation of neoplastic cells in vivo. All of the tumor cells expressed high levels of mRNA for both the putative colony-stimulating factor 1 (CSF-1) receptor (c-fms proto-oncogene product), as well as the c-fos proto-oncogene. Although all of the tumor cells proliferated in culture without the addition of exogenous CSF-1, which is required for the proliferation of primary macrophages partially transformed by the same c-myc retrovirus, several phenotypes were observed with respect to the expression of CSF-1 and granulocyte-macrophage CSF and to their growth factor responsiveness. The proliferation of one tumor, which secreted high levels of CSF-1, was blocked by specific anti-CSF-1 serum. This tumor was found to express altered CSF-1 mRNA and to have a DNA rearrangement at the CSF-1 locus. In this particular case, the data indicate that a CSF-1 gene rearrangement was the secondary event in development of the tumor. The pleiotropy of phenotypes among the other tumors indicated that there are a variety of other mechanisms for such secondary events which can be investigated with this system.

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Molecular dissection of pheromone selectivity in the competence signaling system ComRS of streptococci

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1916085117 ◽

2020 ◽

Vol 117 (14) ◽

pp. 7745-7754

Author(s):

Laura Ledesma-Garcia ◽

Jordhan Thuillier ◽

Armando Guzman-Espinola ◽

Imke Ensinck ◽

Inès Li de la Sierra-Gallay ◽

...

Keyword(s):

Biomedical Applications ◽

Rational Design ◽

Mutational Analysis ◽

Point Mutations ◽

Streptococcus Thermophilus ◽

Activation Mechanism ◽

Toggle Switch ◽

Exogenous Dna ◽

C Terminus ◽

Molecular Determinants

Competence allows bacteria to internalize exogenous DNA fragments for the acquisition of new phenotypes such as antibiotic resistance or virulence traits. In most streptococci, competence is regulated by ComRS signaling, a system based on the mature ComS pheromone (XIP), which is internalized to activate the (R)RNPP-type ComR sensor by triggering dimerization and DNA binding. Cross-talk analyses demonstrated major differences of selectivity between ComRS systems and raised questions concerning the mechanism of pheromone-sensor recognition and coevolution. Here, we decipher the molecular determinants of selectivity of the closely related ComRS systems fromStreptococcus thermophilusandStreptococcus vestibularis. Despite high similarity, we show that the divergence in ComR-XIP interaction does not allow reciprocal activation. We perform the structural analysis of the ComRS system fromS. vestibularis.Comparison with its ortholog fromS. thermophilusreveals an activation mechanism based on a toggle switch involving the recruitment of a key loop by the XIP C terminus. Together with a broad mutational analysis, we identify essential residues directly involved in peptide binding. Notably, we generate a ComR mutant that displays a fully reversed selectivity toward the heterologous pheromone with only five point mutations, as well as other ComR variants featuring XIP bispecificity and/or neofunctionalization for hybrid XIP peptides. We also reveal that a single XIP mutation relaxes the strictness of ComR activation, suggesting fast adaptability of molecular communication phenotypes. Overall, this study is paving the way toward the rational design or directed evolution of artificial ComRS systems for a range of biotechnological and biomedical applications.

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Aberrant (pro)renin receptor expression induces genomic instability in pancreatic ductal adenocarcinoma through upregulation of SMARCA5/SNF2H

Communications Biology ◽

10.1038/s42003-020-01434-x ◽

2020 ◽

Vol 3 (1) ◽

Author(s):

Yuki Shibayama ◽

Kazuo Takahashi ◽

Hisateru Yamaguchi ◽

Jun Yasuda ◽

Daisuke Yamazaki ◽

...

Keyword(s):

Pancreatic Ductal Adenocarcinoma ◽

Genomic Instability ◽

Chromosomal Abnormalities ◽

Point Mutations ◽

Nuclear Bodies ◽

Receptor Expression ◽

Ductal Adenocarcinoma ◽

Structural Variations ◽

Aberrant Expression ◽

Genome Level

Abstract(Pro)renin receptor [(P)RR] has a role in various diseases, such as cardiovascular and renal disorders and cancer. Aberrant (P)RR expression is prevalent in pancreatic ductal adenocarcinoma (PDAC) which is the most common pancreatic cancer. Here we show whether aberrant expression of (P)RR directly leads to genomic instability in human pancreatic ductal epithelial (HPDE) cells. (P)RR-expressing HPDE cells show obvious cellular atypia. Whole genome sequencing reveals that aberrant (P)RR expression induces large numbers of point mutations and structural variations at the genome level. A (P)RR-expressing cell population exhibits tumour-forming ability, showing both atypical nuclei characterised by distinctive nuclear bodies and chromosomal abnormalities. (P)RR overexpression upregulates SWItch/Sucrose Non-Fermentable (SWI/SNF)-related, matrix-associated, actin-dependent regulator of chromatin, subfamily a, member 5 (SMARCA5) through a direct molecular interaction, which results in the failure of several genomic stability pathways. These data reveal that aberrant (P)RR expression contributes to the early carcinogenesis of PDAC.

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Cancer gene profile of metastatic breast cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2012.30.15_suppl.1015 ◽

2012 ◽

Vol 30 (15_suppl) ◽

pp. 1015-1015 ◽

Cited By ~ 2

Author(s):

Funda Meric-Bernstam ◽

Garrett Frampton ◽

Jaime Ferrer-Lozano ◽

Roman Yelensky ◽

Gary A. Palmer ◽

...

Keyword(s):

Breast Cancer ◽

Metastatic Breast Cancer ◽

Cancer Patients ◽

Point Mutations ◽

Metastatic Breast ◽

Genomic Alteration ◽

Genomic Profiling ◽

Genomic Alterations ◽

Primary Tumors ◽

Recurrent Tumors

1015 Background: There is great interest in using genomic information to guide therapy selection in cancer patients. The aim of this study was to determine the spectrum of genomic alterations identified in MBC patients, and evaluate the concordance of alterations between primary and recurrent tumors. Methods: We performed comprehensive profiling on formalin-fixed paraffin embedded samples from 42 patients with MBC using a targeted next generation sequencing (NGS) assay in a CLIA laboratory (Foundation Medicine). Genomic libraries were captured for 3,230 exons in 182 cancer related genes plus 37 introns from 14 genes often rearranged in cancer and sequenced to an average depth of 390X with 99% of bases covered >100X. In total 30 primary and 37 recurrent tumors were profiled, including 3 separate recurrences in 1 patient and matched primary-recurrences in 22 patients. Point mutations, indels, copy number alterations and rearrangements were assessed. Alterations that are targetable with established or investigational therapeutics were considered “actionable”. Results: At least 1 genomic alteration was identified in all but 2 breast samples (both primary tumors). Point mutations were identified in several cancer-related genes including PIK3CA, TP53, PTEN, CDH1, ARID1A, AKT1, NF1, FBXW7 and FGFR3. Amplification was observed in HER2; 11 of 12 HER2 IHC positive samples were found to have HER2 gains by NGS; in addition, a HER2 gain was identified by NGS in a HER2- (1+ IHC) sample. Amplification of PIK3CA, IGF1R, FGFR2, AKT2, MDM2, and MCL1 plus a CDKN2A homozygous deletion were also identified. While the majority of known driver alterations (85%) were concordant in the matched pairs of primary and recurrent tumors, in 11 of 22 sets there was at least 1 discordant driver alteration, and these included both gains and losses of potential therapeutic targets. Overall 32 of 42 patients (76%) had an actionable genomic alteration. Conclusions: Genomic profiling of breast cancer samples reveals genomic alterations in most metastatic breast cancer patients. Over three quarters of patients have actionable findings, suggesting that genomic profiling may assist in individualized pathway-directed therapy.

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Enforced expression of the c-myc oncogene inhibits cell differentiation by precluding entry into a distinct predifferentiation state in G0/G1.

Molecular and Cellular Biology ◽

10.1128/mcb.8.4.1614 ◽

1988 ◽

Vol 8 (4) ◽

pp. 1614-1624 ◽

Cited By ~ 162

Author(s):

S O Freytag

Keyword(s):

Cell Cycle ◽

Cell Differentiation ◽

Transcriptional Control ◽

Normal Cells ◽

Myc Oncogene ◽

Rous Sarcoma ◽

Myc Gene ◽

High Concentrations ◽

Arrest Growth ◽

Differentiation Inducers

A broad base of data has implicated a role for the c-myc proto-oncogene in the control of the cell cycle and cell differentiation. To further define the role of myc in these processes, I examined the effect of enforced myc expression on several events that are thought to be important steps leading to the terminally differentiated state: (i) the ability to arrest growth in G0/G1, (ii) the ability to replicate the genome upon initiation of the differentiation program, and (iii) the ability to lose responsiveness to mitogens and withdraw from the cell cycle. 3T3-L1 preadipocyte cell lines expressing various levels of myc mRNA were established by transfection with a recombinant myc gene under the transcriptional control of the Rous sarcoma virus (RSV) promoter. Cells that expressed high constitutive levels of pRSVmyc mRNA arrested in G0/G1 at densities similar to those of normal cells at confluence. Upon initiation of the differentiation program, such cells traversed the cell cycle with kinetics similar to those of normal cells and subsequently arrested in G0/G1. Thus, enforced expression of myc had no effect on the ability of cells to arrest growth in G0/G1 or to replicate the genome upon initiation of the differentiation program. Cells were then tested for their ability to reenter the cell cycle upon exposure to high concentrations of serum and for their capacity to differentiate. In contrast to normal cells, cells expressing high constitutive levels of myc RNA reentered the cell cycle when challenged with 30% serum and failed to terminally differentiate. The block to differentiation could be reversed by high expression of myc antisense RNA, showing that the induced block was specifically due to enforced expression of pRSVmyc. These findings indicate that 3T3-L1 preadipocytes enter a specific state in G0/G1 after treatment with differentiation inducers, into which cells expressing high constitutive levels of myc RNA are precluded from entering. I propose that myc acts as a molecular switch and directs cells to a pathway that can lead to continued proliferation or to terminal differentiation.

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N-myc expression switched off and class I human leukocyte antigen expression switched on after somatic cell fusion of neuroblastoma cells.

Molecular and Cellular Biology ◽

10.1128/mcb.10.10.5416 ◽

1990 ◽

Vol 10 (10) ◽

pp. 5416-5423 ◽

Cited By ~ 23

Author(s):

R Versteeg ◽

C van der Minne ◽

A Plomp ◽

A Sijts ◽

A van Leeuwen ◽

...

Keyword(s):

Neuroblastoma Cell ◽

Neuroblastoma Cells ◽

Human Leukocyte ◽

Antigen Expression ◽

Suppressor Gene ◽

Class I ◽

Class I Mhc ◽

Putative Tumor Suppressor Gene ◽

Myc Oncogene ◽

Myc Gene

Neuroblastomas often show amplification and high expression of the N-myc oncogene. N-myc expression could be explained as a consequence of gene amplification, but an alternative possibility is that expression primarily results from the inactivation or loss of some factor that normally represses the N-myc gene. To test this idea, we fused N-myc-overexpressing neuroblastoma cell lines with lines that do not express N-myc. In the resulting hybrids, N-myc expression turned out to be switched off, although amplified N-myc copies were still present. This suggests that N-myc overexpression in neuroblastomas results, at least in part, from the inactivation of a suppressor gene that is present in normal cells. In rat neuroblastomas, it has been found that N-myc can switch off class I major histocompatibility complex (MHC) expression. Therefore, we analyzed in our hybrid cells whether suppression of N-myc results in reexpression of human class I MHC genes. Because this was found to be the case, the picture emerges of a hierarchic pathway that connects a putative tumor-suppressor gene with the expression of N-myc and consequently of class I MHC, thus affecting the potential immunogenic properties of neuroblastomas.

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Assessing the Binding Affinity of a Small Molecule for the c-Myc oncogene guanine quadruplex for targeted anticancer applications

Inquiry@Queen's Undergraduate Research Conference Proceedings ◽

10.24908/iqurcp.13250 ◽

2019 ◽

Author(s):

Yushi Liang

Keyword(s):

Cellular Proliferation ◽

Binding Constants ◽

Helical Structure ◽

The Body ◽

Cellular Growth ◽

Myc Oncogene ◽

Double Helical Structure ◽

Myc Gene ◽

Phd Thesis ◽

Hydrogen Bonded

Cancer is a group of diseases defined by abnormal cell growth that can invade different tissues and is caused by mutations to certain genes leading to uncontrolled cellular proliferation.[1] Found in all cells, deoxyribonucleic acid (DNA) encodes through five bases the genes needed to make every protein in the body. Aside from its conventional double helical structure, DNA can form higher-order architectures called guanine quadruplexes (G4s). G4s are composed of planar tetrads of four hydrogen-bonded guanines stabilized by a central cation that help limit the expression of cancer-related genes (Figure 1).[2] c-Myc is a gene that is overexpressed in the majority of human cancers.[3] Overexpression of c-Myc upregulates cellular growth and metabolism pathways central to cancer.[3] The region of the c-Myc gene that controls its expression (‘promoter region’) can fold into a G4.[4] Enforcing the folding of the c-Myc promoter into a G4 using small molecules can prevent c-Myc expression leading to cancer. Two years ago, the Petitjean Group made an exciting discovery of a binder which showed uniquely high affinity for G4s, while not associating with duplex DNA.[5] In my research presented here, I am using the fluorescence indicator displacement assay to indirectly assess binding constants and determine the degree of stabilization this binder offered to the c-Myc G4. Knowing the stabilization offered by this binder to c-Myc G4 can allow further research into a second generation of binders for targeted anticancer applications. Figure 1. Planar tetrads of hydrogen-bonded guanines (left) stacked to form a G4 (right). G4-selective binder (yellow). References [1] Miller, D. M.; Thomas, S. D.; Islam, A.; Muench, D.; Sedoris, K. Clin. Canc. Res. 2013, 18, 5546-5553. [2] Ruggiero, E.; Richter, S. N. Nucleic Acids Res. 2018, 46, 3270-3283. [3] Brooks, T. A.; Hurley, L. H. Genes Cancer. 2010, 6, 641-649. [4] You, H.; Wu, J.; Shao, F.; Yan, J. J. Am. Chem. Soc. 2015, 7, 2424-2427. [5] a) Caitlin E. Miron, PhD Thesis, Queen’s University, 2018; b) C. E. Miron, J.-L. Mergny, A. Petitjean, Platinum Compounds for Binding Guanine Quadruplexes, PCT/C2018/051399.

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Frequent c-myc oncogene activation and infrequent presence of Epstein- Barr virus genome in AIDS-associated lymphoma

Blood ◽

10.1182/blood.v72.2.667.bloodjournal722667 ◽

1988 ◽

Vol 72 (2) ◽

pp. 667-671

Author(s):

M Subar ◽

A Neri ◽

G Inghirami ◽

DM Knowles ◽

R Dalla-Favera

Keyword(s):

Epstein Barr Virus ◽

Virus Genome ◽

Gene Rearrangements ◽

High Grade ◽

Histologic Type ◽

Myc Oncogene ◽

Barr Virus ◽

Oncogene Activation ◽

Myc Gene ◽

Epstein Barr

Sixteen cases of histologic intermediate-grade and high-grade AIDS- associated non-Hodgkin's lymphoma (NHL) were studied for the presence and patterns of c-myc gene and bcl-2 locus rearrangements. The presence of Epstein-Barr virus (EBV) sequences and proteins and HTLV-I sequences were also investigated. c-myc gene rearrangements analogous to those observed in sporadic Burkitt lymphomas were detected in 12 of 16 cases. Six of 16 cases had detectable EBV sequences and proteins. None of the cases displayed bcl-2 rearrangements or contained HTLV-I sequences. These data suggest a frequent role for c-myc activation in the pathogenesis of AIDS-associated NHL, independent of histologic type. Conversely, EBV does not appear to be directly involved in lymphomagenesis in the majority of AIDS-associated NHLs.

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