scholarly journals Gene Duplication and Gene Fusion Are Important Drivers of Tumourigenesis during Cancer Evolution

Genes ◽  
2021 ◽  
Vol 12 (9) ◽  
pp. 1376
Author(s):  
Cian Glenfield ◽  
Hideki Innan
Keyword(s):  
Gene Duplication ◽  
Gene Fusion ◽  
Genome Instability ◽  
Current Knowledge ◽  
Rapid Evolution ◽  
Cellular Level ◽  
Cancer Evolution ◽  
Tumour Formation ◽  
Selective Forces ◽  
Drive Gene

Chromosomal rearrangement and genome instability are common features of cancer cells in human. Consequently, gene duplication and gene fusion events are frequently observed in human malignancies and many of the products of these events are pathogenic, representing significant drivers of tumourigenesis and cancer evolution. In certain subsets of cancers duplicated and fused genes appear to be essential for initiation of tumour formation, and some even have the capability of transforming normal cells, highlighting the importance of understanding the events that result in their formation. The mechanisms that drive gene duplication and fusion are unregulated in cancer and they facilitate rapid evolution by selective forces akin to Darwinian survival of the fittest on a cellular level. In this review, we examine current knowledge of the landscape and prevalence of gene duplication and gene fusion in human cancers.

scholarly journals Convergence of oncogenic cooperation at single-cell and single-gene levels drives leukemic transformation

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Yuxuan Liu ◽  
Zhimin Gu ◽  
Hui Cao ◽  
Pranita Kaphle ◽  
Junhua Lyu ◽  
...  
Keyword(s):  
Gene Expression ◽  
Single Cell ◽  
Cancer Progression ◽  
Single Gene ◽  
Myeloid Cell ◽  
Cellular Level ◽  
Integrative Approach ◽  
Cancer Evolution ◽  
Cell Assays

AbstractCancers develop from the accumulation of somatic mutations, yet it remains unclear how oncogenic lesions cooperate to drive cancer progression. Using a mouse model harboring NRasG12D and EZH2 mutations that recapitulates leukemic progression, we employ single-cell transcriptomic profiling to map cellular composition and gene expression alterations in healthy or diseased bone marrows during leukemogenesis. At cellular level, NRasG12D induces myeloid lineage-biased differentiation and EZH2-deficiency impairs myeloid cell maturation, whereas they cooperate to promote myeloid neoplasms with dysregulated transcriptional programs. At gene level, NRasG12D and EZH2-deficiency independently and synergistically deregulate gene expression. We integrate results from histopathology, leukemia repopulation, and leukemia-initiating cell assays to validate transcriptome-based cellular profiles. We use this resource to relate developmental hierarchies to leukemia phenotypes, evaluate oncogenic cooperation at single-cell and single-gene levels, and identify GEM as a regulator of leukemia-initiating cells. Our studies establish an integrative approach to deconvolute cancer evolution at single-cell resolution in vivo.

scholarly journals Role of RNF20 in cancer development and progression – a comprehensive review

2018 ◽  
Vol 38 (4) ◽  
Author(s):  
Gautam Sethi ◽  
Muthu K. Shanmugam ◽  
Frank Arfuso ◽  
Alan Prem Kumar
Keyword(s):  
Mammalian Cells ◽  
Genome Instability ◽  
Current Knowledge ◽  
Strand Break ◽  
Cancer Development ◽  
Transcriptional Elongation ◽  
Histone H2a ◽  
Post Translational Modification ◽  
Cell Renal Cell Carcinoma ◽  
Suppressor Activity

Evolving strategies to counter cancer initiation and progression rely on the identification of novel therapeutic targets that exploit the aberrant genetic changes driving oncogenesis. Several chromatin associated enzymes have been shown to influence post-translational modification (PTM) in DNA, histones, and non-histone proteins. Any deregulation of this core group of enzymes often leads to cancer development. Ubiquitylation of histone H2B in mammalian cells was identified over three decades ago. An exciting really interesting new gene (RING) family of E3 ubiquitin ligases, known as RNF20 and RNF40, monoubiquitinates histone H2A at K119 or H2B at K120, is known to function in transcriptional elongation, DNA double-strand break (DSB) repair processes, maintenance of chromatin differentiation, and exerting tumor suppressor activity. RNF20 is somatically altered in breast, lung, prostate cancer, clear cell renal cell carcinoma (ccRCC), and mixed lineage leukemia, and its reduced expression is a key factor in initiating genome instability; and it also functions as one of the significant driving factors of oncogenesis. Loss of RNF20/40 and H2B monoubiquitination (H2Bub1) is found in several cancers and is linked to an aggressive phenotype, and is also an indicator of poor prognosis. In this review, we summarized the current knowledge of RNF20 in chronic inflammation-driven cancers, DNA DSBs, and apoptosis, and its impact on chromatin structure beyond the single nucleosome level.

Host defense mechanisms induce genome instability leading to rapid evolution in an opportunistic fungal pathogen

2021 ◽  
Author(s):  
Amanda Smith ◽  
Levi Morran ◽  
Meleah A. Hickman
Keyword(s):  
Fungal Pathogen ◽  
Defense Mechanisms ◽  
Large Scale ◽  
Genome Instability ◽  
Rapid Evolution ◽  
Genomic Changes ◽  
Opportunistic Fungal Pathogen ◽  
Immunocompromised Hosts ◽  
Stressful Environments

The ability to generate genetic variation facilitates rapid adaptation in stressful environments. The opportunistic fungal pathogen Candida albicans frequently undergoes large-scale genomic changes, including aneuploidy and loss-of heterozygosity (LOH), following exposure to host environments. However, the specific host factors inducing C. albicans genome instability remain largely unknown. Here, we leveraged the genetic tractability of nematode hosts to investigate whether innate immune components, including antimicrobial peptides (AMPs) and reactive oxygen species (ROS), induced host-associated C. albicans genome instability. C. albicans associated with immunocompetent hosts carried multiple large-scale genomic changes including LOH, whole chromosome, and segmental aneuploidies. In contrast, C. albicans associated with immunocompromised hosts deficient in AMPs or ROS production had reduced LOH frequencies and fewer, if any, additional genomic changes. To evaluate if extensive host-induced genomic changes had long-term consequences for C. albicans adaptation, we experimentally evolved C. albicans in either immunocompetent or immunocompromised hosts and selected for increased virulence. C. albicans evolved in immunocompetent hosts rapidly increased virulence, but not in immunocompromised hosts. Taken together, this work suggests that host-produced ROS and AMPs induces genotypic plasticity in C. albicans which facilitates rapid evolution.

scholarly journals Acute Myeloid Leukemia Stem Cells: The Challenges of Phenotypic Heterogeneity

Cancers ◽  
2020 ◽  
Vol 12 (12) ◽  
pp. 3742
Author(s):  
Marlon Arnone ◽  
Martina Konantz ◽  
Pauline Hanns ◽  
Anna M. Paczulla Stanger ◽  
Sarah Bertels ◽  
...  
Keyword(s):  
Stem Cells ◽  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Current Knowledge ◽  
Phenotypic Variability ◽  
Cellular Level ◽  
Patient Specific ◽  
Heterogeneous Landscape ◽  
Cells Of Origin ◽  
Acute Myeloid

Patients suffering from acute myeloid leukemia (AML) show highly heterogeneous clinical outcomes. Next to variabilities in patient-specific parameters influencing treatment decisions and outcome, this is due to differences in AML biology. In fact, different genetic drivers may transform variable cells of origin and co-exist with additional genetic lesions (e.g., as observed in clonal hematopoiesis) in a variety of leukemic (sub)clones. Moreover, AML cells are hierarchically organized and contain subpopulations of more immature cells called leukemic stem cells (LSC), which on the cellular level constitute the driver of the disease and may evolve during therapy. This genetic and hierarchical complexity results in a pronounced phenotypic variability, which is observed among AML cells of different patients as well as among the leukemic blasts of individual patients, at diagnosis and during the course of the disease. Here, we review the current knowledge on the heterogeneous landscape of AML surface markers with particular focus on those identifying LSC, and discuss why identification and targeting of this important cellular subpopulation in AML remains challenging.

The Role of Free Radicals in Traumatic Brain Injury

2012 ◽  
Vol 15 (3) ◽  
pp. 253-263 ◽  
Author(s):  
Karen M. O’Connell ◽  
Marguerite T. Littleton-Kearney
Keyword(s):  
Traumatic Brain Injury ◽  
Free Radicals ◽  
Free Radical ◽  
Brain Injury ◽  
Current Knowledge ◽  
Cellular Level ◽  
Secondary Brain Injury ◽  
Secondary Injury ◽  
The Military

Traumatic brain injury (TBI) is a significant cause of death and disability in both the civilian and the military populations. The primary impact causes initial tissue damage, which initiates biochemical cascades, known as secondary injury, that expand the damage. Free radicals are implicated as major contributors to the secondary injury. Our review of recent rodent and human research reveals the prominent role of the free radicals superoxide anion, nitric oxide, and peroxynitrite in secondary brain injury. Much of our current knowledge is based on rodent studies, and the authors identified a gap in the translation of findings from rodent to human TBI. Rodent models are an effective method for elucidating specific mechanisms of free radical-induced injury at the cellular level in a well-controlled environment. However, human TBI does not occur in a vacuum, and variables controlled in the laboratory may affect the injury progression. Additionally, multiple experimental TBI models are accepted in rodent research, and no one model fully reproduces the heterogeneous injury seen in humans. Free radical levels are measured indirectly in human studies based on assumptions from the findings from rodent studies that use direct free radical measurements. Further study in humans should be directed toward large samples to validate the findings in rodent studies. Data obtained from these studies may lead to more targeted treatment to interrupt the secondary injury cascades.

scholarly journals Mutant Allele Imbalance in Cancer

2020 ◽  
Vol 5 (1) ◽  
Author(s):  
Craig M. Bielski ◽  
Barry S. Taylor
Keyword(s):  
Cancer Biology ◽  
Mutant Allele ◽  
Tumor Biology ◽  
Cellular Level ◽  
Driver Mutations ◽  
Annual Review ◽  
Publication Date ◽  
Cancer Evolution ◽  
Allele Imbalance ◽  
And Function

The search for somatic mutations that drive the initiation and progression of human tumors has dominated recent cancer research. While much emphasis has been placed on characterizing the prevalence and function of driver mutations, comparatively less is known about their serial genetic evolution. Indeed, study of this phenomenon has largely focused on tumor-suppressor genes recessive at the cellular level or mechanisms of resistance in tumors with mutant oncogenes targeted by therapy. There is, however, a growing appreciation that despite a decades-old presumption of heterozygosity, changes in mutant oncogene zygosity are common and drive dosage and stoichiometry changes that lead to selective growth advantages. Here, we review the recent progress in understanding mutant allele imbalance and its implications for tumor biology, cancer evolution, and response to anticancer therapy. Expected final online publication date for the Annual Review of Cancer Biology, Volume 5 is March 4, 2021. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

The control of gene flow across a narrow hybrid zone: a selective role for chromosomal rearrangement?

1990 ◽  
Vol 68 (8) ◽  
pp. 1761-1769 ◽  
Author(s):  
D. D. Shaw ◽  
A. D. Marchant ◽  
M. L. Arnold ◽  
N. Contreras ◽  
B. Kohlmann
Keyword(s):  
Hybrid Zone ◽  
Environmental Gradients ◽  
Chromosomal Rearrangements ◽  
Cellular Level ◽  
Evolutionary Status ◽  
Genomic Change ◽  
High Frequencies ◽  
Selective Forces ◽  
Adaptive Role ◽  
Chromosomal Profile

Independent molecular, biochemical, and cytological markers have been used to assess the evolutionary status of a narrow hybrid zone between two genomically distinct taxa of the grasshopper Caledia captiva. Despite the extreme narrowness (<1 km) of the hybrid zone when assessed in terms of its chromosomal profile, other diagnostic nuclear and cytoplasmic markers are found at high frequencies in populations up to 400 km beyond the chromosomal limits of the zone. These data suggest that the hybrid zone is very old and capable of moving while still retaining its narrow chromosomal profile. The data also suggest that the chromosomal rearrangements are the principal components maintaining this narrow hybrid zone and that strong selective forces, acting upon the structure of the genome, are involved. Analysis of chromosomal variation has revealed that the Moreton taxon has a complex chromosomal cline in which every chromosome changes from metacentric to acrocentric or telocentric along the cline. We argue that the chromosomal rearrangements which are involved in maintaining the narrow hybrid zone are themselves playing an adaptive role within the population, both as homo- and hetero-zygotes. A model is presented to explain these patterns of genomic change along environmental gradients as an adaptation, probably at the cellular level, to establish a temporal synchrony of events during embryogenesis.

scholarly journals Impact of Salmonella enterica Type III Secretion System Effectors on the Eukaryotic Host Cell

2012 ◽  
Vol 2012 ◽  
pp. 1-36 ◽  
Author(s):  
Francisco Ramos-Morales
Keyword(s):  
Type Iii Secretion ◽  
Salmonella Enterica ◽  
Current Knowledge ◽  
Cellular Level ◽  
Host Cells ◽  
Secretion Systems ◽  
Type Iii ◽  
Cellular Processes ◽  
Type Iii Secretion Systems ◽  
Near Future

Type III secretion systems are molecular machines used by many Gram-negative bacterial pathogens to inject proteins, known as effectors, directly into eukaryotic host cells. These proteins manipulate host signal transduction pathways and cellular processes to the pathogen’s advantage. Salmonella enterica possesses two virulence-related type III secretion systems that deliver more than forty effectors. This paper reviews our current knowledge about the functions, biochemical activities, host targets, and impact on host cells of these effectors. First, the concerted action of effectors at the cellular level in relevant aspects of the interaction between Salmonella and its hosts is analyzed. Then, particular issues that will drive research in the field in the near future are discussed. Finally, detailed information about each individual effector is provided.

scholarly journals Mitochondrial Heterogeneity in the Brain at the Cellular Level

1998 ◽  
Vol 18 (3) ◽  
pp. 231-237 ◽  
Author(s):  
Ursula Sonnewald ◽  
Leif Hertz ◽  
Arne Schousboe
Keyword(s):  
Amino Acid ◽  
Current Knowledge ◽  
Cell Types ◽  
Cellular Level ◽  
Mitochondrial Structure ◽  
Cell Type Specific ◽  
Mitochondrial Heterogeneity ◽  
Specific Tissue ◽  
And Function ◽  
The Brain

Classically, compartmentation of glutamate metabolism in the brain is associated with the fact that neurons and glia exhibit distinct differences with regard to metabolism of this amino acid. The recent use of 13C-labeled compounds to study this metabolism in conjunction with the availability of cell type-specific tissue culture modes has led to the notion that such compartmentation may even be present in individual cell types, neurons as well as glia. To better understand and explain this, it is proposed that mitochondrial heterogeneity may exist resulting in tricarboxylic acid cycles with different properties regarding cycling rates and ratio as well as coupling to amino acid biosynthesis, primarily involving glutamate and aspartate. These hypotheses are evaluated in the light of current knowledge about mitochondrial structure and function.

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