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Frontiers in Immunology 2021Over the last decades, the revolution in DNA sequencing has changed the way we understand the genetics and biology of B-cell lymphomas by uncovering a large number of... (Review)
Review
Over the last decades, the revolution in DNA sequencing has changed the way we understand the genetics and biology of B-cell lymphomas by uncovering a large number of recurrently mutated genes, whose aberrant function is likely to play an important role in the initiation and/or maintenance of these cancers. Dissecting how the involved genes contribute to the physiology and pathology of germinal center (GC) B cells -the origin of most B-cell lymphomas- will be key to advance our ability to diagnose and treat these patients. Genetically engineered mouse models (GEMM) that faithfully recapitulate lymphoma-associated genetic alterations offer a valuable platform to investigate the pathogenic roles of candidate oncogenes and tumor suppressors , and to pre-clinically develop new therapeutic principles in the context of an intact tumor immune microenvironment. In this review, we provide a summary of state-of-the art GEMMs obtained by accurately modelling the most common genetic alterations found in human GC B cell malignancies, with a focus on Burkitt lymphoma, follicular lymphoma, and diffuse large B-cell lymphoma, and we discuss how lessons learned from these models can help guide the design of novel therapeutic approaches for this disease.
Topics: Adoptive Transfer; Animals; Disease Models, Animal; Genes, myc; Genetic Engineering; Germinal Center; Histones; Humans; Lymphoma, B-Cell; Mice; Mutation; Translocation, Genetic; Tumor Microenvironment
PubMed: 34456919
DOI: 10.3389/fimmu.2021.710711 -
Journal of Hepatology Jun 2020Hepatomegaly can be triggered by insulin and insulin-unrelated etiologies. Insulin acts via AKT, but how other challenges cause hepatomegaly is unknown.
BACKGROUND & AIMS
Hepatomegaly can be triggered by insulin and insulin-unrelated etiologies. Insulin acts via AKT, but how other challenges cause hepatomegaly is unknown.
METHODS
Since many hepatomegaly-inducing toxicants and stressors activate NRF2, we examined the effect of NRF2 activation on liver size and metabolism using a conditional allele encoding a constitutively active NRF2 variant to generate Nrf2 mice in which NRF2 is selectively activated in hepatocytes. We also used adenoviruses encoding variants of the autophagy adaptor p62/SQSTM1, which activates liver NRF2, as well as liver-specific ATG7-deficient mice (Atg7) and liver specimens from patients with hepatic sinusoidal obstruction syndrome (HSOS) and autoimmune hepatitis (AIH). RNA sequencing and cell signaling analyses were used to determine cellular consequences of NRF2 activation and diverse histological analyses were used to study effects of the different manipulations on liver and systemic pathophysiology.
RESULTS
Hepatocyte-specific NRF2 activation, due to p62 accumulation or inhibition of KEAP1 binding, led to hepatomegaly associated with enhanced glycogenosis, steatosis and G2/M cell cycle arrest, fostering hyperplasia without cell division. Surprisingly, all manipulations that led to NRF2 activation also activated AKT, whose inhibition blocked NRF2-induced hepatomegaly and glycogenosis, but not NRF2-dependent antioxidant gene induction. AKT activation was linked to NRF2-mediated transcriptional induction of PDGF and EGF receptor ligands that signaled through their cognate receptors in an autocrine manner. Insulin and insulin-like growth factors were not involved. The NRF2-AKT signaling axis was also activated in human HSOS- and AIH-related hepatomegaly.
CONCLUSIONS
NRF2, a transcription factor readily activated by xenobiotics, oxidative stress and autophagy disruptors, may be a common mediator of hepatomegaly; its effects on hepatic metabolism can be reversed by AKT/tyrosine kinase inhibitors.
LAY SUMMARY
Hepatomegaly can be triggered by numerous etiological factors, including infections, liver cancer, metabolic disturbances, toxicant exposure, as well as alcohol abuse or drug-induced hepatitis. This study identified the oxidative stress response transcription factor NRF2 as a common mediator of hepatomegaly. NRF2 activation results in elevated expression of several growth factors. These growth factors are made by hepatocytes and activate their receptors in an autocrine fashion to stimulate the accumulation of glycogen and lipids that lead to hepatocyte and liver enlargement. The protein kinase AKT plays a key role in this process and its inhibition leads to reversal of hepatomegaly.
Topics: Adult; Animals; Autophagy; Disease Models, Animal; ErbB Receptors; Female; Genes, erbB-1; Hemangioma; Hepatic Veno-Occlusive Disease; Hepatitis, Autoimmune; Hepatomegaly; Humans; Liver Neoplasms; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Middle Aged; NF-E2-Related Factor 2; Oxidative Stress; Proto-Oncogene Proteins c-akt; Receptor, Platelet-Derived Growth Factor alpha; Signal Transduction
PubMed: 32105670
DOI: 10.1016/j.jhep.2020.01.023 -
BMC Medical Genomics Nov 2023Chronic inflammation causes bone destruction in middle ear cholesteatomas (MECs). However, the causes of their neoplastic features remain unknown. The present study...
BACKGROUND
Chronic inflammation causes bone destruction in middle ear cholesteatomas (MECs). However, the causes of their neoplastic features remain unknown. The present study demonstrated for the first time that neoplastic features of MEC are based on proto-oncogene mutations.
RESULTS
DNA was extracted from MEC and blood samples of five patients to detect somatic mutations using depth-depth exome sequencing. Exons with somatic variants were analyzed using an additional 17 MEC/blood test pairs. Variants detected in MECs but not in blood were considered pathogenic variant candidates. We analyzed the correlation between proto-oncogene (NOTCH1 and MYC) variants and the presence of bone destruction and granulation tissue formation. MYC and NOTCH1 variants were detected in two and five of the 22 samples, respectively. Two of the NOTCH1 variants were located in its specific functional domain, one was truncating and the other was a splice donor site variant. Mutations of the two genes in attic cholesteatomas (n = 14) were significantly related with bone destruction (p = 0.0148) but not with granulation tissue formation (p = 0.399).
CONCLUSIONS
This is the first study to demonstrate a relationship between neoplastic features of MEC and proto-oncogene mutations.
Topics: Humans; Cholesteatoma, Middle Ear; Ear, Middle; Mutation; Proto-Oncogenes
PubMed: 37968650
DOI: 10.1186/s12920-023-01640-6 -
International Journal of Molecular... Aug 2022The function of the root system is crucial for plant survival, such as anchoring plants, absorbing nutrients and water from the soil, and adapting to stress. MYB... (Review)
Review
The function of the root system is crucial for plant survival, such as anchoring plants, absorbing nutrients and water from the soil, and adapting to stress. MYB transcription factors constitute one of the largest transcription factor families in plant genomes with structural and functional diversifications. Members of this superfamily in plant development and cell differentiation, specialized metabolism, and biotic and abiotic stress processes are widely recognized, but their roles in plant roots are still not well characterized. Recent advances in functional studies remind us that genes may have potentially key roles in roots. In this review, the current knowledge about the functions of genes in roots was summarized, including promoting cell differentiation, regulating cell division through cell cycle, response to biotic and abiotic stresses (e.g., drought, salt stress, nutrient stress, light, gravity, and fungi), and mediate phytohormone signals. genes from the same subfamily tend to regulate similar biological processes in roots in redundant but precise ways. Given their increasing known functions and wide expression profiles in roots, genes are proposed as key components of the gene regulatory networks associated with distinct biological processes in roots. Further functional studies of genes will provide an important basis for root regulatory mechanisms, enabling a more inclusive green revolution and sustainable agriculture to face the constant changes in climate and environmental conditions.
Topics: Gene Expression Regulation, Plant; Genes, myb; Phylogeny; Plant Proteins; Plant Roots; Stress, Physiological; Transcription Factors
PubMed: 36012533
DOI: 10.3390/ijms23169262 -
Cold Spring Harbor Perspectives in... Nov 2021Lung cancer is a heterogeneous disease that is subdivided into histopathological subtypes with distinct behaviors. Each subtype is characterized by distinct features and... (Review)
Review
Lung cancer is a heterogeneous disease that is subdivided into histopathological subtypes with distinct behaviors. Each subtype is characterized by distinct features and molecular alterations that influence tumor metabolism. Alterations in tumor metabolism can be exploited by imaging modalities that use metabolite tracers for the detection and characterization of tumors. Microenvironmental factors, including nutrient and oxygen availability and the presence of stromal cells, are a critical influence on tumor metabolism. Recent technological advances facilitate the direct evaluation of metabolic alterations in patient tumors in this complex microenvironment. In addition, molecular alterations directly influence tumor cell metabolism and metabolic dependencies that influence response to therapy. Current therapeutic approaches to target tumor metabolism are currently being developed and translated into the clinic for patient therapy.
Topics: Adaptation, Physiological; Amino Acids; Blood Glucose; Genes, erbB-1; Genes, p53; Humans; Lung Neoplasms; Molecular Targeted Therapy; Nucleotides; Phenotype; Positron-Emission Tomography; Proto-Oncogene Proteins p21(ras); Tomography, X-Ray Computed; Tumor Microenvironment
PubMed: 34127512
DOI: 10.1101/cshperspect.a037838 -
Cureus Jan 2024Molecular biology shines a light of hope amid the complex terrain of cancer, bringing revolutionary approaches to cancer treatment. Instead of providing a synopsis, this... (Review)
Review
Molecular biology shines a light of hope amid the complex terrain of cancer, bringing revolutionary approaches to cancer treatment. Instead of providing a synopsis, this review presents an engaging story that sheds light on the genetic nuances controlling the course of cancer. This review goes beyond just listing genetic alterations to examine the complex interactions that lead to oncogene activation, exploring particular triggers such as viral infections or proto-oncogene mutations. A comprehensive grasp of the significant influence of oncogenes is possible through the classification and clarification of their function in various types of cancer. Furthermore, the role of tumor suppressor genes in controlling cell division and preventing tumor growth is fully explained, providing concrete examples and case studies to ground the conversation and create a stronger story. This study highlights the practical applications of molecular biology and provides a comprehensive overview of various detection and treatment modalities. It emphasizes the effectiveness of RNA analysis, immunohistochemistry, and next-generation sequencing (NGS) in cancer diagnosis and prognosis prediction. Examples include the individualized classification of breast cancers through RNA profiling, the use of NGS to identify actionable mutations such as epidermal growth factor receptor and anaplastic lymphoma kinase in lung cancer, and the use of immunohistochemical staining for proteins such as Kirsten rat sarcoma viral oncogene to guide treatment decisions in colorectal cancer. This paper carefully examines how molecular biology is essential to creating new strategies to fight this difficult and widespread illness. It highlights the exciting array of available therapeutic approaches, offering concrete instances of how clustered regularly interspaced short palindromic repeats (CRISPR) and CRISPR-associated protein 9 (CRISPR-Cas9), targeted pharmaceuticals, immunotherapy, and treatments that induce apoptosis are driving a paradigm shift in cancer care. The revolutionary CRISPR-Cas9 system takes center stage, showcasing how precise gene editing could transform cancer therapy. This study concludes by fervently highlighting the critical role that molecular biology plays in reducing the complexity of cancer and changing the treatment landscape. It lists accomplishments but also thoughtfully examines cases and findings that progress our search for more precisely customized and effective cancer therapies.
PubMed: 38352075
DOI: 10.7759/cureus.52246 -
Trends in Cancer Dec 2021Rearranged during transfection (RET) is involved in the physiological development of some organ systems. Activating RET alterations via either gene fusions or point... (Review)
Review
Rearranged during transfection (RET) is involved in the physiological development of some organ systems. Activating RET alterations via either gene fusions or point mutations are potent oncogenic drivers in non-small cell lung cancer, thyroid cancer, and in multiple diverse cancers. RET-altered cancers were initially treated with multikinase inhibitors (MKIs). The efficacy of MKIs was modest at the expense of notable toxicities from their off-target activity. Recently, highly potent and RET-specific inhibitors selpercatinib and pralsetinib were successfully translated to the clinic and FDA approved. We summarize the current state-of-the-art therapeutics with preclinical and clinical insights of these novel RET inhibitors, acquired resistance mechanisms, and future outlooks.
Topics: Carcinoma, Non-Small-Cell Lung; Humans; Lung Neoplasms; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-ret; Proto-Oncogenes
PubMed: 34391699
DOI: 10.1016/j.trecan.2021.07.003 -
Nature Communications Feb 2024The MYC oncogene is often dysregulated in human cancer, including hepatocellular carcinoma (HCC). MYC is considered undruggable to date. Here, we comprehensively...
The MYC oncogene is often dysregulated in human cancer, including hepatocellular carcinoma (HCC). MYC is considered undruggable to date. Here, we comprehensively identify genes essential for survival of MYC but not MYC cells by a CRISPR/Cas9 genome-wide screen in a MYC-conditional HCC model. Our screen uncovers novel MYC synthetic lethal (MYC-SL) interactions and identifies most MYC-SL genes described previously. In particular, the screen reveals nucleocytoplasmic transport to be a MYC-SL interaction. We show that the majority of MYC-SL nucleocytoplasmic transport genes are upregulated in MYC murine HCC and are associated with poor survival in HCC patients. Inhibiting Exportin-1 (XPO1) in vivo induces marked tumor regression in an autochthonous MYC-transgenic HCC model and inhibits tumor growth in HCC patient-derived xenografts. XPO1 expression is associated with poor prognosis only in HCC patients with high MYC activity. We infer that MYC may generally regulate and require altered expression of nucleocytoplasmic transport genes for tumorigenesis.
Topics: Humans; Mice; Animals; Carcinoma, Hepatocellular; Liver Neoplasms; Proto-Oncogene Proteins c-myc; Genes, myc; Cell Transformation, Neoplastic; Carcinogenesis; Cell Line, Tumor; Gene Expression Regulation, Neoplastic
PubMed: 38302473
DOI: 10.1038/s41467-024-45128-y -
Journal of Hematology & Oncology Aug 2021MYC oncogene is a transcription factor with a wide array of functions affecting cellular activities such as cell cycle, apoptosis, DNA damage response, and... (Review)
Review
MYC oncogene is a transcription factor with a wide array of functions affecting cellular activities such as cell cycle, apoptosis, DNA damage response, and hematopoiesis. Due to the multi-functionality of MYC, its expression is regulated at multiple levels. Deregulation of this oncogene can give rise to a variety of cancers. In this review, MYC regulation and the mechanisms by which MYC adjusts cellular functions and its implication in hematologic malignancies are summarized. Further, we also discuss potential inhibitors of MYC that could be beneficial for treating hematologic malignancies.
Topics: Animals; Antineoplastic Agents; Apoptosis; Cell Cycle; DNA Damage; Drug Discovery; Gene Expression Regulation, Neoplastic; Genes, myc; Hematologic Neoplasms; Humans; Models, Molecular; Prognosis; Proto-Oncogene Proteins c-myc
PubMed: 34372899
DOI: 10.1186/s13045-021-01111-4 -
Cancer Chemotherapy and Pharmacology Aug 2023Aberrant alterations of ERBB receptor tyrosine kinases lead to tumorigenesis. Single agent therapy targeting EGFR or HER2 has shown clinical successes, but drug...
A phase I trial of the pan-ERBB inhibitor neratinib combined with the MEK inhibitor trametinib in patients with advanced cancer with EGFR mutation/amplification, HER2 mutation/amplification, HER3/4 mutation or KRAS mutation.
PURPOSE
Aberrant alterations of ERBB receptor tyrosine kinases lead to tumorigenesis. Single agent therapy targeting EGFR or HER2 has shown clinical successes, but drug resistance often develops due to aberrant or compensatory mechanisms. Herein, we sought to determine the feasibility and safety of neratinib and trametinib in patients with EGFR mutation/amplification, HER2 mutation/amplification, HER3/4 mutation and KRAS mutation.
METHODS
Patients with actionable somatic mutations or amplifications in ERBB genes or actionable KRAS mutations were enrolled to receive neratinib and trametinib in this phase I dose escalation trial. The primary endpoint was determination of the maximum tolerated dose (MTD) and dose-limiting toxicity (DLT). Secondary endpoints included pharmacokinetic analysis and preliminary anti-tumor efficacy.
RESULTS
Twenty patients were enrolled with a median age of 50.5 years and a median of 3 lines of prior therapy. Grade 3 treatment-related toxicities included: diarrhea (25%), vomiting (10%), nausea (5%), fatigue (5%) and malaise (5%). The MTD was dose level (DL) minus 1 (neratinib 160 mg daily with trametinib 1 mg, 5 days on and 2 days off) given 2 DLTs of grade 3 diarrhea in DL1 (neratinib 160 mg daily with trametinib 1 mg daily). The treatment-related toxicities of DL1 included: diarrhea (100%), nausea (55.6%) and rash (55.6%). Pharmacokinetic data showed trametinib clearance was significantly reduced leading to high drug exposures of trametinib. Two patients achieved stable disease (SD) ≥ 4 months.
CONCLUSION
Neratinib and trametinib combination was toxic and had limited clinical efficacy. This may be due to suboptimal drug dosing given drug-drug interactions.
TRIAL REGISTRATION ID
NCT03065387.
Topics: Humans; Middle Aged; Proto-Oncogene Proteins p21(ras); Antineoplastic Combined Chemotherapy Protocols; Neoplasms; Protein Kinase Inhibitors; Genes, erbB; Mutation; ErbB Receptors; Nausea; Diarrhea; Mitogen-Activated Protein Kinase Kinases; Receptor, ErbB-2
PubMed: 37314501
DOI: 10.1007/s00280-023-04545-4