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Blood Feb 2023Chromosomal rearrangements involving the MDS1 and EVI1 complex locus (MECOM) on chromosome 3q26 define an aggressive subtype of acute myeloid leukemia (AML) that is...
Chromosomal rearrangements involving the MDS1 and EVI1 complex locus (MECOM) on chromosome 3q26 define an aggressive subtype of acute myeloid leukemia (AML) that is associated with chemotherapy resistance and dismal prognosis. Established treatment regimens commonly fail in these patients, therefore, there is an urgent need for new therapeutic concepts that will require a better understanding of the molecular and cellular functions of the ecotropic viral integration site 1 (EVI1) oncogene. To characterize gene regulatory functions of EVI1 and associated dependencies in AML, we developed experimentally tractable human and murine disease models, investigated the transcriptional consequences of EVI1 withdrawal in vitro and in vivo, and performed the first genome-wide CRISPR screens in EVI1-dependent AML. By integrating conserved transcriptional targets with genetic dependency data, we identified and characterized the ETS transcription factor ERG as a direct transcriptional target of EVI1 that is aberrantly expressed and selectively required in both human and murine EVI1-driven AML. EVI1 controls the expression of ERG and occupies a conserved intragenic enhancer region in AML cell lines and samples from patients with primary AML. Suppression of ERG induces terminal differentiation of EVI1-driven AML cells, whereas ectopic expression of ERG abrogates their dependence on EVI1, indicating that the major oncogenic functions of EVI1 are mediated through aberrant transcriptional activation of ERG. Interfering with this regulatory axis may provide entry points for the development of rational targeted therapies.
Topics: Humans; Animals; Mice; DNA-Binding Proteins; MDS1 and EVI1 Complex Locus Protein; Proto-Oncogenes; Transcription Factors; Leukemia, Myeloid, Acute; Carcinogenesis; Transcriptional Regulator ERG
PubMed: 36095844
DOI: 10.1182/blood.2022016592 -
Nature Jun 2023Target occupancy is often insufficient to elicit biological activity, particularly for RNA, compounded by the longstanding challenges surrounding the molecular...
Target occupancy is often insufficient to elicit biological activity, particularly for RNA, compounded by the longstanding challenges surrounding the molecular recognition of RNA structures by small molecules. Here we studied molecular recognition patterns between a natural-product-inspired small-molecule collection and three-dimensionally folded RNA structures. Mapping these interaction landscapes across the human transcriptome defined structure-activity relationships. Although RNA-binding compounds that bind to functional sites were expected to elicit a biological response, most identified interactions were predicted to be biologically inert as they bind elsewhere. We reasoned that, for such cases, an alternative strategy to modulate RNA biology is to cleave the target through a ribonuclease-targeting chimera, where an RNA-binding molecule is appended to a heterocycle that binds to and locally activates RNase L. Overlay of the substrate specificity for RNase L with the binding landscape of small molecules revealed many favourable candidate binders that might be bioactive when converted into degraders. We provide a proof of concept, designing selective degraders for the precursor to the disease-associated microRNA-155 (pre-miR-155), JUN mRNA and MYC mRNA. Thus, small-molecule RNA-targeted degradation can be leveraged to convert strong, yet inactive, binding interactions into potent and specific modulators of RNA function.
Topics: Humans; Genes, jun; Genes, myc; MicroRNAs; Nucleic Acid Conformation; RNA, Messenger; Structure-Activity Relationship; Substrate Specificity; Endoribonucleases; Transcriptome
PubMed: 37225982
DOI: 10.1038/s41586-023-06091-8 -
Science (New York, N.Y.) May 2021The 1986 Chernobyl nuclear power plant accident increased papillary thyroid carcinoma (PTC) incidence in surrounding regions, particularly for radioactive iodine...
The 1986 Chernobyl nuclear power plant accident increased papillary thyroid carcinoma (PTC) incidence in surrounding regions, particularly for radioactive iodine (I)-exposed children. We analyzed genomic, transcriptomic, and epigenomic characteristics of 440 PTCs from Ukraine (from 359 individuals with estimated childhood I exposure and 81 unexposed children born after 1986). PTCs displayed radiation dose-dependent enrichment of fusion drivers, nearly all in the mitogen-activated protein kinase pathway, and increases in small deletions and simple/balanced structural variants that were clonal and bore hallmarks of nonhomologous end-joining repair. Radiation-related genomic alterations were more pronounced for individuals who were younger at exposure. Transcriptomic and epigenomic features were strongly associated with driver events but not radiation dose. Our results point to DNA double-strand breaks as early carcinogenic events that subsequently enable PTC growth after environmental radiation exposure.
Topics: Adolescent; Adult; Chernobyl Nuclear Accident; Child; Child, Preschool; DNA Copy Number Variations; Epigenome; Female; Gene Expression Profiling; Genes, ras; Genetic Variation; Humans; Infant; Iodine Radioisotopes; Loss of Heterozygosity; Male; Middle Aged; Mutation; Neoplasms, Radiation-Induced; Proto-Oncogene Proteins B-raf; RNA-Seq; Radiation Dosage; Thyroid Cancer, Papillary; Thyroid Gland; Thyroid Neoplasms; Translocation, Genetic; Ukraine; Whole Genome Sequencing; Young Adult
PubMed: 33888599
DOI: 10.1126/science.abg2538 -
Frontiers in Immunology 2022Chronic rhinosinusitis with nasal polyps (CRSwNP) is a common sinonasal inflammatory disorder with high heterogeneity. Increasing evidence have indicated that the...
BACKGROUND
Chronic rhinosinusitis with nasal polyps (CRSwNP) is a common sinonasal inflammatory disorder with high heterogeneity. Increasing evidence have indicated that the infiltration of macrophages especially M2 macrophages play pivotal roles in the pathogenesis of CRSwNP, but the underlying mechanisms remain undetermined. This study sought to identify potential biomarkers related to M2 macrophages in CRSwNP.
METHODS
The expression datasets of GSE136825 and GSE179265 were download from Gene Expression Omnibus (GEO) database and merged. Then, CIBERSORT and weighted gene co-expression network analysis (WGCNA) algorithms were applied to identify M2 macrophage-related gene modules. Thereafter, differentially expressed genes (DEGs) related to M2 macrophages were selected to perform functional enrichment analyses. A protein-protein interaction (PPI) network was built to identify hub genes and quantitative real-time reverse transcriptions PCR was used to verify the bioinformatics results.
RESULTS
A total of 92 DEGs associated with M2 macrophages were identified for further analysis. The results of Gene ontology (GO) and Kyoto Encyclopedia of genes and genomes (KEGG) analyses illustrated that M2 macrophage-associated DEGs primarily enriched in immune responses and extracellular matrix structure. PPI network analysis identified 18 hub genes related to M2 macrophages that might be pivotal in the pathogenesis of CRSwNP. After verification, AIF1, C1QA, C1QB, C3AR1, CCR1, CD163, CD4, CD53, CD86, CSF1R, CYBB, FCER1G, FCGR3A, IL10RA, ITGB2, LAPTM5, PLEK, TYROBP were identified as potential M2 macrophage-related biomarkers for CRSwNP.
CONCLUSION
These findings yield new insights into the hub genes and mechanisms related to M2 macrophages in the pathogenesis of CRSwNP. Further studies of these hub genes would help better understand the disease progression and identify potential treatment targets.
Topics: Humans; Nasal Polyps; Sinusitis; Genes, fms; Chronic Disease; Macrophages
PubMed: 36466903
DOI: 10.3389/fimmu.2022.1047930 -
Molecular Cancer May 2023Neuroblastoma is the most common solid tumor in infants accounting for approximately 15% of all cancer-related deaths. Over 50% of high-risk neuroblastoma relapse,...
BACKGROUND
Neuroblastoma is the most common solid tumor in infants accounting for approximately 15% of all cancer-related deaths. Over 50% of high-risk neuroblastoma relapse, emphasizing the need of novel drug targets and therapeutic strategies. In neuroblastoma, chromosomal gains at chromosome 17q, including IGF2BP1, and MYCN amplification at chromosome 2p are associated with adverse outcome. Recent, pre-clinical evidence indicates the feasibility of direct and indirect targeting of IGF2BP1 and MYCN in cancer treatment.
METHODS
Candidate oncogenes on 17q were identified by profiling the transcriptomic/genomic landscape of 100 human neuroblastoma samples and public gene essentiality data. Molecular mechanisms and gene expression profiles underlying the oncogenic and therapeutic target potential of the 17q oncogene IGF2BP1 and its cross-talk with MYCN were characterized and validated in human neuroblastoma cells, xenografts and PDX as well as novel IGF2BP1/MYCN transgene mouse models.
RESULTS
We reveal a novel, druggable feedforward loop of IGF2BP1 (17q) and MYCN (2p) in high-risk neuroblastoma. This promotes 2p/17q chromosomal gains and unleashes an oncogene storm resulting in fostered expression of 17q oncogenes like BIRC5 (survivin). Conditional, sympatho-adrenal transgene expression of IGF2BP1 induces neuroblastoma at a 100% incidence. IGF2BP1-driven malignancies are reminiscent to human high-risk neuroblastoma, including 2p/17q-syntenic chromosomal gains and upregulation of Mycn, Birc5, as well as key neuroblastoma circuit factors like Phox2b. Co-expression of IGF2BP1/MYCN reduces disease latency and survival probability by fostering oncogene expression. Combined inhibition of IGF2BP1 by BTYNB, MYCN by BRD inhibitors or BIRC5 by YM-155 is beneficial in vitro and, for BTYNB, also.
CONCLUSION
We reveal a novel, druggable neuroblastoma oncogene circuit settling on strong, transcriptional/post-transcriptional synergy of MYCN and IGF2BP1. MYCN/IGF2BP1 feedforward regulation promotes an oncogene storm harboring high therapeutic potential for combined, targeted inhibition of IGF2BP1, MYCN expression and MYCN/IGF2BP1-effectors like BIRC5.
Topics: Animals; Humans; Infant; Mice; Cell Line, Tumor; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Genes, myc; N-Myc Proto-Oncogene Protein; Neoplasm Recurrence, Local; Neuroblastoma
PubMed: 37246217
DOI: 10.1186/s12943-023-01792-0 -
Radiology and Oncology Sep 2019Background Colorectal cancer is a successful model of genetic biomarker development in oncology. Currently, several predictive or prognostic genetic alterations have... (Review)
Review
Background Colorectal cancer is a successful model of genetic biomarker development in oncology. Currently, several predictive or prognostic genetic alterations have been identified and are used in clinical practice. The RAS gene family, which includes KRAS and NRAS act as predictors for anti-epithelial growth factor receptor treatment (anti-EGFR), and it has been suggested that NRAS mutations also play a role in prognosis: patients harboring NRAS alterations have a significantly shorter survival compared to those with wild type tumours. BRAF V600E mutations are rare and occur mostly in tumors located in the ascending colon in elderly female patients. BRAF is instrumental in establishing prognosis: survival is shorter by 10-16 months in BRAF-mutant patients, and BRAF may be a negative prognostic factor for patients who undergo hepatic or pulmonary metastasectomy. Moreover, this mutation is used as a negative predictive factor for anti-EGFR therapies. Two new biomarkers have recently been added to the metastatic colorectal cancer panel: HER2 and microsatellite instability. While HER2 is still being investigated in different prospective studies in order to validate its prognostic role, microsatellite instability already guides clinical decisions in substituted with advanced colorectal cancer. Conclusions There are current evidences that support using above mentioned genetic biomarkers to better identify the right medicine that is supposed to be used in the right patient. This approach contributes to a more individualized patient-oriented treatment in daily clinical practice.
Topics: Antineoplastic Agents, Immunological; Antineoplastic Combined Chemotherapy Protocols; Cetuximab; Colorectal Neoplasms; ErbB Receptors; Female; Genes, erbB-2; Genes, ras; Genetic Markers; Humans; Ipilimumab; Male; Microsatellite Instability; Mutation; Panitumumab; Prognosis; Proto-Oncogene Proteins B-raf; Sex Factors; Trastuzumab
PubMed: 31553708
DOI: 10.2478/raon-2019-0033 -
Nature Communications May 2022c-MYC (MYC) is a major driver of prostate cancer tumorigenesis and progression. Although MYC is overexpressed in both early and metastatic disease and associated with...
c-MYC (MYC) is a major driver of prostate cancer tumorigenesis and progression. Although MYC is overexpressed in both early and metastatic disease and associated with poor survival, its impact on prostate transcriptional reprogramming remains elusive. We demonstrate that MYC overexpression significantly diminishes the androgen receptor (AR) transcriptional program (the set of genes directly targeted by the AR protein) in luminal prostate cells without altering AR expression. Analyses of clinical specimens reveal that concurrent low AR and high MYC transcriptional programs accelerate prostate cancer progression toward a metastatic, castration-resistant disease. Data integration of single-cell transcriptomics together with ChIP-seq uncover an increase in RNA polymerase II (Pol II) promoter-proximal pausing at AR-dependent genes following MYC overexpression without an accompanying deactivation of AR-bound enhancers. Altogether, our findings suggest that MYC overexpression antagonizes the canonical AR transcriptional program and contributes to prostate tumor initiation and progression by disrupting transcriptional pause release at AR-regulated genes.
Topics: Cell Line, Tumor; Cell Transformation, Neoplastic; Gene Expression Regulation, Neoplastic; Genes, myc; Humans; Male; Prostate; Prostatic Neoplasms; Proto-Oncogene Proteins c-myc; Receptors, Androgen
PubMed: 35562350
DOI: 10.1038/s41467-022-30257-z -
Cancer Cell Mar 2024KRAS inhibitors (adagrasib and sotorasib) have shown clinical promise in targeting KRAS-mutated lung cancers; however, most patients eventually develop resistance. In...
KRAS inhibitors (adagrasib and sotorasib) have shown clinical promise in targeting KRAS-mutated lung cancers; however, most patients eventually develop resistance. In lung patients with adenocarcinoma with KRAS and STK11/LKB1 co-mutations, we find an enrichment of the squamous cell carcinoma gene signature in pre-treatment biopsies correlates with a poor response to adagrasib. Studies of Lkb1-deficient KRAS and Kras lung cancer mouse models and organoids treated with KRAS inhibitors reveal tumors invoke a lineage plasticity program, adeno-to-squamous transition (AST), that enables resistance to KRAS inhibition. Transcriptomic and epigenomic analyses reveal ΔNp63 drives AST and modulates response to KRAS inhibition. We identify an intermediate high-plastic cell state marked by expression of an AST plasticity signature and Krt6a. Notably, expression of the AST plasticity signature and KRT6A at baseline correlates with poor adagrasib responses. These data indicate the role of AST in KRAS inhibitor resistance and provide predictive biomarkers for KRAS-targeted therapies in lung cancer.
Topics: Animals; Mice; Humans; Proto-Oncogene Proteins p21(ras); Lung Neoplasms; Genes, ras; Carcinoma, Squamous Cell; Mutation; Acetonitriles; Piperazines; Pyrimidines
PubMed: 38402609
DOI: 10.1016/j.ccell.2024.01.012 -
Nature Dec 2022Squamous cell carcinomas are triggered by marked elevation of RAS-MAPK signalling and progression from benign papilloma to invasive malignancy. At tumour-stromal...
Squamous cell carcinomas are triggered by marked elevation of RAS-MAPK signalling and progression from benign papilloma to invasive malignancy. At tumour-stromal interfaces, a subset of tumour-initiating progenitors, the cancer stem cells, obtain increased resistance to chemotherapy and immunotherapy along this pathway. The distribution and changes in cancer stem cells during progression from a benign state to invasive squamous cell carcinoma remain unclear. Here we show in mice that, after oncogenic RAS activation, cancer stem cells rewire their gene expression program and trigger self-propelling, aberrant signalling crosstalk with their tissue microenvironment that drives their malignant progression. The non-genetic, dynamic cascade of intercellular exchanges involves downstream pathways that are often mutated in advanced metastatic squamous cell carcinomas with high mutational burden. Coupling our clonal skin HRAS mouse model with single-cell transcriptomics, chromatin landscaping, lentiviral reporters and lineage tracing, we show that aberrant crosstalk between cancer stem cells and their microenvironment triggers angiogenesis and TGFβ signalling, creating conditions that are conducive for hijacking leptin and leptin receptor signalling, which in turn launches downstream phosphoinositide 3-kinase (PI3K)-AKT-mTOR signalling during the benign-to-malignant transition. By functionally examining each step in this pathway, we reveal how dynamic temporal crosstalk with the microenvironment orchestrated by the stem cells profoundly fuels this path to malignancy. These insights suggest broad implications for cancer therapeutics.
Topics: Animals; Mice; Carcinoma, Squamous Cell; Genes, ras; Leptin; Neoplastic Stem Cells; Neovascularization, Pathologic; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; ras Proteins; Signal Transduction; Transforming Growth Factor beta; Tumor Microenvironment
PubMed: 36450983
DOI: 10.1038/s41586-022-05475-6 -
American Journal of Hematology Apr 2021Venetoclax (Ven) is a selective small-molecule inhibitor of BCL-2 that exhibits antitumoral activity against MM cells with t(11;14) translocation. We evaluated the...
Venetoclax (Ven) is a selective small-molecule inhibitor of BCL-2 that exhibits antitumoral activity against MM cells with t(11;14) translocation. We evaluated the safety and efficacy of Ven and dexamethasone (VenDex) combination in patients with t(11;14) positive relapsed/refractory (R/R) multiple myeloma (MM). This open-label, multicenter study had two distinct phases (phase one [P1], phase two [P2]). Patients in both phases received VenDex (oral Ven 800 mg/day + oral Dex 40 mg [20 mg for patients ≥75 years] on days 1, 8, and 15, per 21-day cycle). The primary objective of the P1 VenDex cohort was to assess safety and pharmacokinetics. Phase two further evaluated efficacy with objective response rate (ORR) and very good partial response or better. Correlative studies explored baseline BCL2 (BCL-2) and BCL2L1 (BCL-X ) gene expression, cytogenetics, and recurrent somatic mutations in MM. Twenty and 31 patients in P1 and P2 with t(11;14) positive translocation received VenDex. P1/P2 patients had received a median of 3/5 lines of prior therapy, and 20%/87% were refractory to daratumumab. Predominant grade 3/4 hematological adverse events (AEs) with ≥10% occurrence included lymphopenia (20%/19%), neutropenia (15%/7%), thrombocytopenia (10%/10%), and anemia (5%/16%). At a median follow-up of 12.3/9.2 months, ORR was 60%/48%. The duration of response estimate at 12 months was 50%/61%, and the median time to progression was 12.4/10.8 months. In biomarker evaluable patients, response to VenDex was independent of concurrent del(17p) or gain(1q) and mutations in key oncogenic signaling pathways, including MAPK and NF-kB. VenDex demonstrated efficacy and manageable safety in heavily-pre-treated patients with t(11;14) R/R MM.
Topics: Aged; Antibodies, Monoclonal; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow; Bridged Bicyclo Compounds, Heterocyclic; Chromosomes, Human, Pair 11; Chromosomes, Human, Pair 14; Combined Modality Therapy; Dexamethasone; Female; Follow-Up Studies; Genes, bcl-2; Hematologic Diseases; Hematopoietic Stem Cell Transplantation; Humans; Infections; Kaplan-Meier Estimate; Male; Middle Aged; Multiple Myeloma; Neoplasm Proteins; Proto-Oncogene Proteins c-bcl-2; Recurrence; Salvage Therapy; Signal Transduction; Sulfonamides; Translocation, Genetic; bcl-X Protein
PubMed: 33368455
DOI: 10.1002/ajh.26083