• Animal biotechnology
• Animal models
• CRISPR/Cas9
• Disease models
• Genetic modification
• Genome editing
• Transgenic animals

• Humans
• Animals
• Mice
• Biomedical Research
• Gene Editing
• Models, Animal

• 22-15-00227 Russian Science Foundation
• 075-15-2021-668 UNU Transgenbank

• High-grade B-cell lymphoma
• MYC
• MYC therapies
• double expressor lymphoma

• artemisinin
• cell death
• chemotherapy
• leukemia
• oncogenes
• sesquiterpenoids

• MYC synthetic lethality
• RNA therapeutics
• quadratic phenotypic optimization platform
• splice‐switch oligonucleotides

Cancer genome sequencing has identified dozens of mutations with a putative role in lymphomagenesis and leukemogenesis. Validation of driver mutations responsible for B cell neoplasms is complicated by the volume of mutations worthy of investigation and by the complex ways that multiple mutations arising from different stages of B cell development can cooperate. Forward and reverse genetic strategies in mice can provide complementary validation of human driver genes and in some cases comparative genomics of these models with human tumors has directed the identification of new drivers in human malignancies. We review a collection of forward genetic screens performed using insertional mutagenesis, chemical mutagenesis and exome sequencing and discuss how the high coverage of subclonal mutations in insertional mutagenesis screens can identify cooperating mutations at rates not possible using human tumor genomes. We also compare a set of independently conducted screens from Pax5 mutant mice that converge upon a common set of mutations observed in human acute lymphoblastic leukemia (ALL). We also discuss reverse genetic models and screens that use CRISPR-Cas, ORFs and shRNAs to provide high throughput in vivo proof of oncogenic function, with an emphasis on models using adoptive transfer of ex vivo cultured cells. Finally, we summarize mouse models that offer temporal regulation of candidate genes in an in vivo setting to demonstrate the potential of their encoded proteins as therapeutic targets.

• B cell leukemia
• B cell lymphoma
• CRISPR-Cas
• exome sequencing
• insertional mutagenesis
• mouse models
• reverse genetics
• shRNA

• MYC downregulation
• MYC inhibition
• epigenetics
• multiple myeloma
• targeted therapies
• transcription factor
• undruggable target

• PTMs
• Phenotype reversion
• Revertant
• SIAH1
• TCTP1
• Tumor reversion

• TAR/2018/001054 Science and Engineering Research Board
• EMR/2017/004018 Science and Engineering Research Board
• 5/13/38/2014-NCD-III Indian Council of Medical Research
• 5/13/38/2014 NCDIII-Eoffice73143 Indian Council of Medical Research
• 573(CSIR-UGC NET JUNE 2017 University Grants Commission
• 09/045(1672)/2019-EMR-I Council of Scientific and Industrial Research, India
• 09/045(1622)/2019-EMR-I Council of Scientific and Industrial Research, India

• Alzheimer’s disease
• Brain
• MYC
• Neurodegenerative diseases
• Neuronal degeneration
• Neuronal repair

• MYC
• cancer
• computational
• drug targets
• synthetic lethality

E3 ubiquitin ligases are of interest as drug targets due to their involvement in the regulation of the functions and interactions of several proteins. Various E3 ligase complexes are considered oncogenes or tumor suppressors associated with the development of melanoma. These proteins regulate the functions of various signaling pathways and proteins, such as p53 and Notch. The aim of the present study was to determine the expression levels of F-box and WD repeat domain-containing 7 (FBXW7), c-Myc, MDM2 and p53 proteins in samples from patients with dysplastic nevi or melanoma, and to evaluate their association with clinicopathological parameters and prognosis of the disease. Paraffin blocks with postoperative material from 100 patients diagnosed with dysplastic moles or melanoma were used in the present study. Tissue microarrays and immunohistochemistry were used to examine FBXW7, c-Myc, MDM2 and p53 protein expression. The results revealed that there was significantly lower FBXW7 expression in advanced melanoma compared with dysplastic nevus, melanoma in situ and stage pT1 melanoma (P<0.001). Additionally, there was a statistically significant association between the expression levels of FBXW7 and the morphological type of the tumor (P<0.001). In addition, there was a strong positive association between FBXW7 expression and the changes in c-Myc expression (P<0.02), and a strong trend was observed between decreased FBXW7 expression and a higher risk of death in patients, with the major factor in patient mortality being the stages of melanoma. Additionally, p53 expression was associated with the depth of melanoma invasion and the morphological type of the tumor. In summary, FBXW7 expression exhibited the highest statistically significant prognostic value and associations with advanced melanoma. As the majority of FBXW7 substrates are oncoproteins, their degradation by FBXW7 may highlight these proteins as potential targets for the treatment of melanoma.

• F-box and WD repeat domain-containing 7
• MDM2
• c-Myc
• melanoma
• p53
• prognostic factor
• ubiquitin ligases

• MYC
• cancer
• immune response
• immunoediting
• immunotolerance

Gastric cancer (GC) is the third leading cause of cancer-related death. Although the therapeutic approaches have improved, the 5-year survival rate of GC patients after surgical resection remains low due to the high rates of metastasis and recurrence. Patients with schizophrenia have significantly lower incidences of cancer after long-term drug treatment, suggesting the potential or partially ameliorate the risk of cancer development of antipsychotic drugs. The goal of this study was to explore antipsychotic drugs with an optional effective therapy against gastric cellular carcinoma. We found that sertindole, an atypical antipsychotic, exhibited anti-tumor efficacy on human GC cells in vitro and in vivo. Moreover, sertindole in combination with cisplatin dramatically enhanced apoptosis-induction in GC cells. In addition, the pro-apoptotic effect of sertindole on GC might in part, involved in inhibition of STAT3 activation and downstream signals, including Mcl1, surviving, c-Myc, cyclin D1. Collectively, these results suggested that sertindole could be a potential anticancer reagent and be an attractive therapeutic adjuvant for the treatment of human GC.

• cell apoptosis
• cisplatin
• gastric cancer
• sertindole

• HSP90 inhibition
• STA-9090
• c-Myc
• esophageal squamous cell cancer
• patient-derived xenograft model
• Ganetespib

• LIC activity
• Myc
• Notch pathway
• T-cell acute leukemia
• Wnt signaling
• β-catenin

The oncoprotein transcription factor MYC is a validated but challenging anticancer target. In this work, we show that WDR5—a well-structured protein with druggable pockets—could be a focal point for effective anti-MYC therapies. We demonstrate that WDR5 recruits MYC to chromatin to control the expression of genes connected to protein synthesis, a process that is arguably deregulated in all cancers. We also show that disrupting the interaction between MYC and WDR5 causes existing tumors to regress. These findings raise the possibility that the MYC–WDR5 nexus could be targeted to treat cancer.

The oncoprotein transcription factor MYC is overexpressed in the majority of cancers. Key to its oncogenic activity is the ability of MYC to regulate gene expression patterns that drive and maintain the malignant state. MYC is also considered a validated anticancer target, but efforts to pharmacologically inhibit MYC have failed. The dependence of MYC on cofactors creates opportunities for therapeutic intervention, but for any cofactor this requires structural understanding of how the cofactor interacts with MYC, knowledge of the role it plays in MYC function, and demonstration that disrupting the cofactor interaction will cause existing cancers to regress. One cofactor for which structural information is available is WDR5, which interacts with MYC to facilitate its recruitment to chromatin. To explore whether disruption of the MYC–WDR5 interaction could potentially become a viable anticancer strategy, we developed a Burkitt's lymphoma system that allows replacement of wild-type MYC for mutants that are defective for WDR5 binding or all known nuclear MYC functions. Using this system, we show that WDR5 recruits MYC to chromatin to control the expression of genes linked to biomass accumulation. We further show that disrupting the MYC–WDR5 interaction within the context of an existing cancer promotes rapid and comprehensive tumor regression in vivo. These observations connect WDR5 to a core tumorigenic function of MYC and establish that, if a therapeutic window can be established, MYC–WDR5 inhibitors could be developed as anticancer agents.

• MYC
• cancer
• cancer therapy
• chromatin
• lymphoma

• interleukin receptor common gamma subunit
• lymphoma
• mice
• murine leukemia viruses
• severe combined immunodeficiency

Cardiac glycosides are approved for the treatment of heart failure as Na⁺/K⁺ pump inhibitors. Their repurposing in oncology is currently investigated in preclinical and clinical studies. However, the identification of a specific cancer type defined by a molecular signature to design targeted clinical trials with cardiac glycosides remains to be characterized. Here, we demonstrate that cardiac glycoside proscillaridin A specifically targets MYC overexpressing leukemia cells and leukemia stem cells by causing MYC degradation, epigenetic reprogramming and leukemia differentiation through loss of lysine acetylation.

Proscillaridin A anticancer activity was investigated against a panel of human leukemia and solid tumor cell lines with different MYC expression levels, overexpression in vitro systems and leukemia stem cells. RNA-sequencing and differentiation studies were used to characterize transcriptional and phenotypic changes. Drug-induced epigenetic changes were studied by chromatin post-translational modification analysis, expression of chromatin regulators, chromatin immunoprecipitation, and mass-spectrometry.

At a clinically relevant dose, proscillaridin A rapidly altered MYC protein half-life causing MYC degradation and growth inhibition. Transcriptomic profile of leukemic cells after treatment showed a downregulation of genes involved in MYC pathways, cell replication and an upregulation of hematopoietic differentiation genes. Functional studies confirmed cell cycle inhibition and the onset of leukemia differentiation even after drug removal. Proscillaridin A induced a significant loss of lysine acetylation in histone H3 (at lysine 9, 14, 18 and 27) and in non-histone proteins such as MYC itself, MYC target proteins, and a series of histone acetylation regulators. Global loss of acetylation correlated with the rapid downregulation of histone acetyltransferases. Importantly, proscillaridin A demonstrated anticancer activity against lymphoid and myeloid stem cell populations characterized by MYC overexpression.

Overall, these results strongly support the repurposing of proscillaridin A in MYC overexpressing leukemia.

The online version of this article (10.1186/s13046-019-1242-8) contains supplementary material, which is available to authorized users.

• Cardiac glycosides
• Chromatin remodelling
• Leukemia
• Leukemia stem cells
• Lysine acetylation
• Lysine acetyltransferase
• MYC
• Proscillaridin A

• Hepatocellular carcinoma (HCC)
• Hepatocellular cholangiocarcinoma
• MYC
• NF-κB
• NF-κB essential modulator (NEMO)

Gastric cancer (GC) ranks as the third leading cause of cancer-related mortality worldwide, and approximately 42% of all cases diagnosed each year worldwide are diagnosed in China. A large number of clinical applications have revealed that Trametes robiniophila Μurr. (Huaier) exhibits an anti-tumour effect. However, loss of the bioactive components of Huaier during the extraction procedure with water is unavoidable, and the underlying mechanism of the anti-cancer effect of Huaier remains poorly understood. In this study, we investigated the anti-cancer effect of Huaier n-butanol extract, which contained 51.4% total flavonoids, on HGC27, MGC803, and AGS human GC cell lines in vitro. At a low concentration, Huaier n-butanol extract inhibited the growth of these GC cell types, induced cell cycle arrest and reduced cell metastasis. Moreover, Huaier n-butanol extract suppressed the c-Myc-Bmi1 signalling pathway, and overexpression of Bmi1 reversed the effects of Huaier n-butanol extract on GC cells. Thus, our findings indicate that Huaier n-butanol extract suppresses the proliferation and metastasis of GC cells via a c-Myc-Bmi1-mediated approach, providing a new perspective for our understanding of the anti-tumour effects of Huaier. These results suggest that Huaier n-butanol extract could be an attractive therapeutic adjuvant for the treatment of human GC.

• AP4
• Cell death
• Cellular senescence
• c-Myc

c‐Myc is one of the major human proto‐oncogenes and is often associated with tumor aggression and poor clinical outcome. Paradoxically, Myc was also reported as a suppressor of cell motility, invasiveness, and metastasis. Among the direct targets of Myc are many components of the protein synthesis machinery whose induction results in an overall increase in protein synthesis that empowers tumor cell growth. At present, it is largely unknown whether beyond the global enhancement of protein synthesis, Myc activation results in translation modulation of specific genes. Here, we measured Myc‐induced global changes in gene expression at the transcription, translation, and protein levels and uncovered extensive transcript‐specific regulation of protein translation. Particularly, we detected a broad coordination between regulation of transcription and translation upon modulation of Myc activity and showed the connection of these responses to mTOR signaling to enhance oncogenic transformation and to the TGFβ pathway to modulate cell migration and invasiveness. Our results elucidate novel facets of Myc‐induced cellular responses and provide a more comprehensive view of the consequences of its activation in cancer cells.

• c‐Myc
• metastasis
• transcriptional responses
• transformation
• translational regulation

Deregulated c-Myc expression is a hallmark of many human cancers. We have recently identified a role of mammalian homolog of yeast SPT-ADA-GCN5-acetyltransferas (SAGA) complex component, SAGA-associated factor 29 (SGF29), in regulating the c-Myc overexpression. Here, we discuss the molecular nature of SFG29 in SPT3-TAF9-GCN5-acetyltransferase complex, a counterpart of yeast SAGA complex, and the mechanism through which the elevated SGF29 expression contribute to oncogenic potential of c-Myc in hepatocellularcarcinoma (HCC). We propose that the upstream regulation of SGF29 elicited by sex-determining region Y (Sry) is also augmented in HCC. We hypothesize that c-Myc elevation driven by the deregulated Sry and SGF29 pathway is implicated in the male specific acquisition of human HCCs.

• c-Myc
• SPT3-TAF9-GCN5-acetyltransferase complex
• SGF29
• Sry
• Hepatocarcinogenesis

• MYC Oncogene
• oncogene addiction
• targeted therapeutics
• transgenic mouse models

• oncogene addiction
• myc
• tumor recurrence
• tumor microenvironment
• tumor immunology

• Animals
• Cell Transformation, Neoplastic/genetics
• Cell Transformation, Neoplastic/immunology
• Humans
• Immune System
• Immunologic Surveillance
• Molecular Targeted Therapy
• Neoplasms/genetics
• Neoplasms/immunology
• Neoplasms/pathology
• Neoplasms/therapy
• Oncogene Proteins/antagonists & inhibitors
• Oncogene Proteins/genetics
• Tumor Microenvironment/genetics
• Tumor Microenvironment/immunology

• CA 112973 NCI NIH HHS
• U56 CA112973 NCI NIH HHS
• P01 CA034233 NCI NIH HHS
• R01 CA089305 NCI NIH HHS
• CA 114747 NCI NIH HHS
• U54CA149145 NCI NIH HHS
• F32 CA177139 NCI NIH HHS
• R01 CA105102 NCI NIH HHS
• AI007290 NIAID NIH HHS
• F32CA177139 NCI NIH HHS
• U54 CA149145 NCI NIH HHS
• 5 T32 AI07290 NIAID NIH HHS
• 170378 PQ22 PHS HHS
• U54CA143907 NCI NIH HHS
• 105102 PHS HHS
• P50 CA114747 NCI NIH HHS
• U54 CA143907 NCI NIH HHS
• R01 CA170378 NCI NIH HHS
• R01 CA 089305 NCI NIH HHS
• U01 CA188383 NCI NIH HHS

• AKT
• Barr virus
• Burkitt’s lymphoma
• Epstein
• PI3-kinase
• c-MYC
• mTOR

The dependence on the overexpression of a single oncogene constitutes an exploitable weakness for molecular targeted therapy. These drugs can produce dramatic tumor regression by targeting the driving oncogene, but relapse often follows. Understanding the complex interactions of the tumor's multifaceted response to oncogene inactivation is key to tumor regression. It has become clear that a collection of cellular responses lead to regression and that immune-mediated steps are vital to preventing relapse. Our integrative mathematical model includes a variety of cellular response mechanisms of tumors to oncogene inactivation. It allows for correct predictions of the time course of events following oncogene inactivation and their impact on tumor burden. A number of aspects of our mathematical model have proven to be necessary for recapitulating our experimental results. These include a number of heterogeneous tumor cell states since cells following different cellular programs have vastly different fates. Stochastic transitions between these states are necessary to capture the effect of escape from oncogene addiction (i.e., resistance). Finally, delay differential equations were used to accurately model the tumor growth kinetics that we have observed. We use this to model oncogene addiction in MYC-induced lymphoma, osteosarcoma, and hepatocellular carcinoma.

• myc
• mouse models
• cancer

• Animals
• Antineoplastic Agents/pharmacology
• Cell Transformation, Neoplastic/metabolism
• Cell Transformation, Neoplastic/pathology
• Disease Models, Animal
• Humans
• Mice
• Molecular Targeted Therapy
• Proto-Oncogene Proteins c-myc/antagonists & inhibitors
• Proto-Oncogene Proteins c-myc/metabolism
• Signal Transduction/drug effects

• 11650 Cancer Research UK
• 12481 Cancer Research UK

Complex phenotypes emerge from the interactions of thousands of macromolecules that are organized in multimolecular complexes and interacting functional modules. In turn, modules form functional networks in health and disease. Omics approaches collect data on changes for all genes and proteins and statistical analysis attempts to uncover the functional modules that perform the functions that characterize higher levels of biological organization. Systems biology attempts to transcend the study of individual genes/proteins and to integrate them into higher order information. Cancer cells exhibit defective genetic and epigenetic networks formed by altered complexes and network modules arising in different parts of tumor tissues that sustain autonomous cell behavior which ultimately lead tumor growth. We suggest that an understanding of tumor behavior must address not only molecular but also, and more importantly, tumor cell heterogeneity, by considering cancer tissue genetic and epigenetic networks, by characterizing changes in the types, composition, and interactions of complexes and networks in the different parts of tumor tissues, and by identifying critical hubs that connect them in time and space.

• Cell cycle
• complex
• cyclin-dependent kinase
• cyclin-dependent kinase inhibitors signaling
• module
• network
• oncogene
• oncoprotein
• system
• tumor suppressor gene
• tumor suppressor protein

• Animals
• Blotting, Southern
• Embryonic Stem Cells
• Flow Cytometry
• Genes, myc
• Humans
• Mice
• Mice, Inbred C57BL
• Mice, Transgenic
• Phenotype
• Polymerase Chain Reaction
• Proto-Oncogene Mas
• Proto-Oncogene Proteins c-myc/genetics

• Animals
• Cell Proliferation/drug effects
• Chemical Warfare Agents/toxicity
• Cholinesterase Inhibitors/administration & dosage
• Cholinesterase Inhibitors/toxicity
• Colon/drug effects
• Colon/enzymology
• Colon/metabolism
• Colon/pathology
• Down-Regulation
• Enterocytes/drug effects
• Enterocytes/enzymology
• Enterocytes/metabolism
• Injections, Intramuscular
• Lethal Dose 50
• MAP Kinase Signaling System/drug effects
• Male
• Proto-Oncogene Proteins c-jun/metabolism
• Proto-Oncogene Proteins c-myc/metabolism
• Rats
• Rats, Wistar
• Soman/administration & dosage
• Soman/toxicity
• Time Factors
• ets-Domain Protein Elk-1/metabolism
• p38 Mitogen-Activated Protein Kinases/metabolism

• Animals
• Disease Models, Animal
• Mice
• Mice, Transgenic
• Neoplasm Proteins/genetics
• Neoplasm Proteins/metabolism
• Neoplasms/drug therapy
• Neoplasms/metabolism
• Oncogenes
• Signal Transduction

• Animals
• Cell Transformation, Neoplastic
• Homeodomain Proteins
• Leukemia-Lymphoma, Adult T-Cell/etiology
• Lymphoma, T-Cell/etiology
• Lymphoma, T-Cell/pathology
• Mice
• Mice, Knockout
• Proto-Oncogene Proteins c-myc
• Receptors, Notch
• T-Lymphocytes/pathology
• Thymus Gland/cytology
• beta Catenin/physiology

• P30 DK34928 NIDDK NIH HHS
• R01 CA104547 NCI NIH HHS
• P30 DK034928 NIDDK NIH HHS
• R01 CA104547-01A1 NCI NIH HHS
• R01 AI059676-01 NIAID NIH HHS
• R01 AI059676 NIAID NIH HHS

• Blotting, Western
• Burkitt Lymphoma/etiology
• Chromatin Immunoprecipitation
• Gene Expression Profiling
• Gene Expression Regulation, Neoplastic/physiology
• Genes, myc/physiology
• Humans
• Interferon-beta/pharmacology
• Microarray Analysis
• NF-kappa B/genetics
• Neoplasm Proteins/genetics
• Promoter Regions, Genetic
• Proto-Oncogene Mas
• RNA, Messenger/metabolism
• Reverse Transcriptase Polymerase Chain Reaction
• STAT1 Transcription Factor/genetics
• STAT1 Transcription Factor/metabolism
• Tumor Cells, Cultured

• Intramural NIH HHS

• Animals
• Brain Neoplasms/drug therapy
• Brain Neoplasms/genetics
• Brain Neoplasms/physiopathology
• Cell Cycle Proteins/metabolism
• Drug Design
• Glioma/drug therapy
• Glioma/genetics
• Glioma/physiopathology
• Humans
• Molecular Biology
• Neoplastic Stem Cells
• Neovascularization, Pathologic
• Signal Transduction

• Animals
• Chromosome Aberrations
• Chromosome Mapping
• Chromosomes/genetics
• Chromosomes/radiation effects
• Gamma Rays/adverse effects
• Genetic Predisposition to Disease/genetics
• In Situ Hybridization
• Lymphoma/etiology
• Lymphoma/genetics
• Mice
• Mice, Inbred C57BL
• Neoplasms, Radiation-Induced/genetics
• Oligonucleotide Array Sequence Analysis
• Radiation Dosage