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1

Grandori, C. "Myc target genes." Trends in Biochemical Sciences 22, no. 5 (1997): 177–81. http://dx.doi.org/10.1016/s0968-0004(97)01025-6.

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2

Stockinger, Susanne, Sabine Hartl, Manfred Koegl, Johannes Zuber, and Matthias Samwer. "Abstract 4284: Determining selectivity of MYC inhibitors via transcriptional monitoring of sentinel genes." Cancer Research 85, no. 8_Supplement_1 (2025): 4284. https://doi.org/10.1158/1538-7445.am2025-4284.

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Abstract MYC is a key transcription factor with essential roles in development and tissue maintenance. Deregulation of MYC has been described in many cancers and several MYC inhibitors have been published, but their selectivity has often remained unclear. A key challenge is the short half-life of MYC mRNA and protein, making MYC particularly sensitive to general transcriptional and translational stress. Therefore, discrimination between on- and off-target effects on MYC and its transcriptional output is critical. Here, we used SLAMseq-derived direct target genes of MYC to establish a panel of sentinel genes to quantify direct and selective effects on MYC. Changes in transcriptional output of MYC are measurable within a few hours after various treatments and can discriminate between on-target MYC perturbation and off-target cytotoxic effects. We then used the assay to benchmark selectivity of various pre-clinical MYC inhibitors. Importantly, the assay principle can be transferred to other important transcription factor drug targets. Citation Format: Susanne Stockinger, Sabine Hartl, Manfred Koegl, Johannes Zuber, Matthias Samwer. Determining selectivity of MYC inhibitors via transcriptional monitoring of sentinel genes [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 4284.
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3

Liu, Zhihui, Xiyuan Zhang, Man Xu, et al. "MYCN drives oncogenesis by cooperating with the histone methyltransferase G9a and the WDR5 adaptor to orchestrate global gene transcription." PLOS Biology 22, no. 3 (2024): e3002240. http://dx.doi.org/10.1371/journal.pbio.3002240.

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MYCN activates canonical MYC targets involved in ribosome biogenesis, protein synthesis, and represses neuronal differentiation genes to drive oncogenesis in neuroblastoma (NB). How MYCN orchestrates global gene expression remains incompletely understood. Our study finds that MYCN binds promoters to up-regulate canonical MYC targets but binds to both enhancers and promoters to repress differentiation genes. MYCN binding also increases H3K4me3 and H3K27ac on canonical MYC target promoters and decreases H3K27ac on neuronal differentiation gene enhancers and promoters. WDR5 facilitates MYCN promoter binding to activate canonical MYC target genes, whereas MYCN recruits G9a to enhancers to repress neuronal differentiation genes. Targeting both MYCN’s active and repressive transcriptional activities using both WDR5 and G9a inhibitors synergistically suppresses NB growth. We demonstrate that MYCN cooperates with WDR5 and G9a to orchestrate global gene transcription. The targeting of both these cofactors is a novel therapeutic strategy to indirectly target the oncogenic activity of MYCN.
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4

Rimpi, S., and J. A. Nilsson. "Metabolic enzymes regulated by the Myc oncogene are possible targets for chemotherapy or chemoprevention." Biochemical Society Transactions 35, no. 2 (2007): 305–10. http://dx.doi.org/10.1042/bst0350305.

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The Myc oncogenes are dysregulated in 70% of human cancers. They encode transcription factors that bind to E-box sequences in DNA, driving the expression of a vast amount of target genes. The biological outcome is enhanced proliferation (which is counteracted by apoptosis), angiogenesis and cancer. Based on the biological effects of Myc overexpression it was originally assumed that the important Myc target genes are those encoding components of the cell cycle machinery. Recent work has challenged this notion and indicates that Myc target genes encoding metabolic enzymes deserve attention, as they may be critical arbiters of Myc in cancer. Thus targeting metabolic enzymes encoded by Myc-target genes may provide a new means to treat cancer that have arisen in response to deregulated Myc oncogenes.
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5

Bueno, María J., Marta Gómez de Cedrón, Gonzalo Gómez-López, et al. "Combinatorial effects of microRNAs to suppress the Myc oncogenic pathway." Blood 117, no. 23 (2011): 6255–66. http://dx.doi.org/10.1182/blood-2010-10-315432.

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Abstract Many mammalian transcripts contain target sites for multiple miRNAs, although it is not clear to what extent miRNAs may coordinately regulate single genes. We have mapped the interactions between down-regulated miRNAs and overexpressed target protein-coding genes in murine and human lymphomas. Myc, one of the hallmark oncogenes in these lymphomas, stands out as the up-regulated gene with the highest number of genetic interactions with down-regulated miRNAs in mouse lymphomas. The regulation of Myc by several of these miRNAs is confirmed by cellular and reporter assays. The same approach identifies MYC and multiple Myc targets as a preferential target of down-regulated miRNAs in human Burkitt lymphoma, a pathology characterized by translocated MYC oncogenes. These results indicate that several miRNAs must be coordinately down-regulated to enhance critical oncogenes, such as Myc. Some of these Myc-targeting miRNAs are repressed by Myc, suggesting that these tumors are a consequence of the unbalanced activity of Myc versus miRNAs.
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6

Nathan, Monica, Ahmed Mahmoud, Nancy BJ Arthur, Agata Gruszczynska, Stephen Sykes, and Francesca Ferraro. "Identification of MYC-Driven Vulnerabilities in Acute Myeloid Leukemia." Blood 144, Supplement 1 (2024): 1336. https://doi.org/10.1182/blood-2024-205860.

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We1 and others2 have shown that MYC is a critical oncogene implicated in the pathogenesis of acute myeloid leukemia (AML). Gain-of-function mutations in Mac box I generate transplantable myeloid leukemia in mice with phenotypic characteristics similar to the overexpression of wild-type Myc. In this study, we aimed to identify a set of biologically distinct, non-redundant, direct MYC transcriptional targets critical for AML maintenance, referred to as the MYC-Leukemogenic Signature (MYC-LS). To identify direct transcriptional targets essential for leukemogenesis, we performed an integrated analysis of the chromatin binding and gene expression profiles of pre-leukemic stem cells expressing oncogenic levels of wild-type or mutated MYC protein. We compared these profiles to those of normal murine hematopoietic progenitor cells. We validated these targets in fully transformed murine myeloid leukemia cells using both bulk and single-cell RNA sequencing. We then analyzed MYC-LS gene expression in human AML samples from the TCGA dataset and evaluated their functional relevance using DepMap Public 22Q4 Chronos Scores. Finally, we performed knockdown studies of selected targets in independent murine cell lines. We identified 858 differentially expressed direct MYC targets (ANOVA, log FC > ±2, FDR < 0.05), with 472 upregulated and 386 downregulated in pre-leukemic hematopoietic progenitor cells compared to normal hematopoietic progenitor cells. GO-Elite analysis identified distinct clusters of dysregulated genes. Cluster 1 genes, upregulated in pre-leukemia cells, were enriched for nucleolar genes, pseudouridinylation genes, and nucleocytoplasmic transport genes. Cluster 2 genes, downregulated in pre-leukemia cells, were enriched for cell communication and immune genes. Of these genes, 135 were direct MYC transcriptional targets, comprising the MYC-Leukemogenic Signature (MYC-LS), including 133 protein-coding genes, one long non-coding RNA, and one microRNA. These targets showed significant changes in expression in MYC-overexpressing HSPCs (116 upregulated, 19 downregulated). Subcellular localization analysis revealed predominant nuclear localization for 77 out of 135 MYC-LS genes, including components of the H/ACA snoRNP complex and pseudouridine synthases pathways. We examined the MYC-LS in human AML samples from the TCGA dataset and analyzed their functional relevance using DepMap Public 22Q4 Chronos Scores. In human AML samples, 107 out of 135 MYC-LS genes significantly correlated with MYC mRNA levels (Pearson correlation coefficients 0.24-0.73, Bonferroni p-value < 0.05). Hierarchical clustering indicated significant dysregulation of 131 out of 135 MYC-LS genes in AML cells compared to normal human myeloid counterparts (FDR < 0.05). DepMap analysis showed that 85 MYC-LS genes were essential for at least one myeloid cell line (median essentiality score -0.5, p < 0.01), with 5 of the top 10 dependencies being genes in the nucleotide synthesis pathway. CTP synthase 1 (CTPS1), a gene involved in cellular response to cytarabine, a chemotherapy drug with the highest efficacy against AML cells, was identified as the top AML-specific dependency, validating the relevance of the MYC-LS genes as potential therapeutic targets. shRNA-mediated inhibition of selected MYC-LS targets significantly inhibited the growth of murine AML1 cells (murine leukemia driven by Dnmt3a and Flt3-ITD) and Mll-Af9 leukemias. Our study describes the MYC-Leukemogenic Signature, a set of direct MYC target genes dysregulated in both murine and human AML cells. These genes are primarily involved in nucleotide synthesis, RNA metabolism, and inflammatory responses, and they are critical for leukemia cell survival and correlate with MYC expression. Importantly, our findings suggest that MYC mutations activate potentially targetable pathways in AML. 1 -Arthur NB, et al. Clin Cancer Res. 2024 Jun 7. doi: 10.1158/1078-0432.CCR-24-0926. 2- Freie B, et al. doi: 10.1101/gad.351292.123
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7

Hu, Yang, Yinteng Wu, Fu Gan, et al. "Identification of Potential Therapeutic Target Genes in Osteoarthritis." Evidence-Based Complementary and Alternative Medicine 2022 (August 13, 2022): 1–15. http://dx.doi.org/10.1155/2022/8027987.

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Objective. Osteoarthritis (OA), also known as joint failure, is characterized by joint pain and, in severe cases, can lead to loss of joint function in patients. Immune-related genes and immune cell infiltration play a crucial role in OA development. We used bioinformatics approaches to detect potential diagnostic markers and available drugs for OA while initially exploring the immune mechanisms of OA. Methods. The training set GSE55235 and validation set GSE51588 and GSE55457 were obtained from the Gene Expression Omnibus (GEO) database and differentially expressed genes (DEGs) were identified by the limma package. Gene set enrichment analysis (GSEA) was performed on the GSE55235 dataset using the cluster profiler package. At the same time, DEGs were analyzed by gene ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG). In addition, protein-protein interaction (PPI) analysis was performed on the common DEGs of the three datasets using the STRING database. Proteins with direct linkage were identified as hub genes, and the relation of hub genes was subsequently analyzed using the GOSemSim package. Hub genes’ expression profiles and diagnostic capabilities (ROC curves) were analyzed and validated using three datasets. In addition, we performed RT-qPCR to validate the levels of hub genes. The immune microenvironment was analyzed using the CIBERSORT package, and the relationship between hub genes and immune cells was evaluated. In addition, we used a linkage map (CMAP) database to identify available drug candidates. Finally, the GSEA of hub genes was used to decipher the potential pathways corresponding to hub genes. Results. Three hub genes (CX3CR1, MYC, and TLR7) were identified. CX3CR1 and TLR7 were highly expressed in patients with OA, whereas the expression of MYC was low. The results of RT-qPCR validation were consistent with those obtained using datasets. Among these genes, CX3CR1 and TLR7 can be used as diagnostic markers. It was found that CX3CR1, MYC, and TLR7 affect the immune microenvironment of OA via different immune cells. In addition, we identified a potential drug for the treatment of OA. Altogether, CX3CR1, MYC, and TLR7 affect the immune response of OA through multiple pathways. Conclusion. CX3CR1, MYC, and TLR7 are associated with various immune cells and are the potential diagnostic markers and therapeutic targets for OA.
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8

Gerlach, Jennifer M., Michael Furrer, Maria Gallant, et al. "PAF1 complex component Leo1 helps recruit Drosophila Myc to promoters." Proceedings of the National Academy of Sciences 114, no. 44 (2017): E9224—E9232. http://dx.doi.org/10.1073/pnas.1705816114.

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The Myc oncogene is a transcription factor with a powerful grip on cellular growth and proliferation. The physical interaction of Myc with the E-box DNA motif has been extensively characterized, but it is less clear whether this sequence-specific interaction is sufficient for Myc’s binding to its transcriptional targets. Here we identify the PAF1 complex, and specifically its component Leo1, as a factor that helps recruit Myc to target genes. Since the PAF1 complex is typically associated with active genes, this interaction with Leo1 contributes to Myc targeting to open promoters.
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9

Robaina, Mazzoccoli, and Esteves Klumb. "Germinal Centre B Cell Functions and Lymphomagenesis: Circuits Involving MYC and MicroRNAs." Cells 8, no. 11 (2019): 1365. http://dx.doi.org/10.3390/cells8111365.

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Background: The transcription factor MYC regulates several biological cellular processes, and its target gene network comprises approximately 15% of all human genes, including microRNAs (miRNAs), that also contribute to MYC regulatory activity. Although miRNAs are emerging as key regulators of immune functions, the specific roles of miRNAs in the regulation/dysregulation of germinal centre B-cells and B-cell lymphomas are still being uncovered. The regulatory network that integrates MYC, target genes and miRNAs is a field of intense study, highlighting potential pathways to be explored in the context of future clinical approaches. Methods: The scientific literature that is indexed in PUBMED was consulted for publications involving MYC and miRNAs with validated bioinformatics analyses or experimental protocols. Additionally, seminal studies on germinal centre B-cell functions and lymphomagenesis were reported. Conclusions: This review summarizes the interactions between MYC and miRNAs through regulatory loops and circuits involving target genes in germinal centre B-cell lymphomas with MYC alterations. Moreover, we provide an overview of the understanding of the regulatory networks between MYC and miRNAs, highlighting the potential implication of this approach for the comprehension of germinal centre B-cell lymphoma pathogenesis. Therefore, circuits involving MYC, target genes and miRNAs provide novel insight into lymphomagenesis that could be useful for new improved therapeutic strategies.
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10

Yuan, Ye, Mohammad Alzrigat, Aida Rodriguez-Garcia, et al. "Target Genes of c-MYC and MYCN with Prognostic Power in Neuroblastoma Exhibit Different Expressions during Sympathoadrenal Development." Cancers 15, no. 18 (2023): 4599. http://dx.doi.org/10.3390/cancers15184599.

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Deregulation of the MYC family of transcription factors c-MYC (encoded by MYC), MYCN, and MYCL is prevalent in most human cancers, with an impact on tumor initiation and progression, as well as response to therapy. In neuroblastoma (NB), amplification of the MYCN oncogene and over-expression of MYC characterize approximately 40% and 10% of all high-risk NB cases, respectively. However, the mechanism and stage of neural crest development in which MYCN and c-MYC contribute to the onset and/or progression of NB are not yet fully understood. Here, we hypothesized that subtle differences in the expression of MYCN and/or c-MYC targets could more accurately stratify NB patients in different risk groups rather than using the expression of either MYC gene alone. We employed an integrative approach using the transcriptome of 498 NB patients from the SEQC cohort and previously defined c-MYC and MYCN target genes to model a multigene transcriptional risk score. Our findings demonstrate that defined sets of c-MYC and MYCN targets with significant prognostic value, effectively stratify NB patients into different groups with varying overall survival probabilities. In particular, patients exhibiting a high-risk signature score present unfavorable clinical parameters, including increased clinical risk, higher INSS stage, MYCN amplification, and disease progression. Notably, target genes with prognostic value differ between c-MYC and MYCN, exhibiting distinct expression patterns in the developing sympathoadrenal system. Genes associated with poor outcomes are mainly found in sympathoblasts rather than in chromaffin cells during the sympathoadrenal development.
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11

Satoh, Kiyotoshi, Shinichi Yachida, Masahiro Sugimoto, et al. "Global metabolic reprogramming of colorectal cancer occurs at adenoma stage and is induced by MYC." Proceedings of the National Academy of Sciences 114, no. 37 (2017): E7697—E7706. http://dx.doi.org/10.1073/pnas.1710366114.

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Cancer cells alter their metabolism for the production of precursors of macromolecules. However, the control mechanisms underlying this reprogramming are poorly understood. Here we show that metabolic reprogramming of colorectal cancer is caused chiefly by aberrant MYC expression. Multiomics-based analyses of paired normal and tumor tissues from 275 patients with colorectal cancer revealed that metabolic alterations occur at the adenoma stage of carcinogenesis, in a manner not associated with specific gene mutations involved in colorectal carcinogenesis. MYC expression induced at least 215 metabolic reactions by changing the expression levels of 121 metabolic genes and 39 transporter genes. Further, MYC negatively regulated the expression of genes involved in mitochondrial biogenesis and maintenance but positively regulated genes involved in DNA and histone methylation. Knockdown of MYC in colorectal cancer cells reset the altered metabolism and suppressed cell growth. Moreover, inhibition of MYC target pyrimidine synthesis genes such as CAD, UMPS, and CTPS blocked cell growth, and thus are potential targets for colorectal cancer therapy.
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12

Zirin, Jonathan, Xiaochun Ni, Laura M. Sack, et al. "Interspecies analysis of MYC targets identifies tRNA synthetases as mediators of growth and survival in MYC-overexpressing cells." Proceedings of the National Academy of Sciences 116, no. 29 (2019): 14614–19. http://dx.doi.org/10.1073/pnas.1821863116.

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Aberrant MYC oncogene activation is one of the most prevalent characteristics of cancer. By overlapping datasets of Drosophila genes that are insulin-responsive and also regulate nucleolus size, we enriched for Myc target genes required for cellular biosynthesis. Among these, we identified the aminoacyl tRNA synthetases (aaRSs) as essential mediators of Myc growth control in Drosophila and found that their pharmacologic inhibition is sufficient to kill MYC-overexpressing human cells, indicating that aaRS inhibitors might be used to selectively target MYC-driven cancers. We suggest a general principle in which oncogenic increases in cellular biosynthesis sensitize cells to disruption of protein homeostasis.
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13

Johansen, Lisa M., Atsushi Iwama, Tracey A. Lodie та ін. "c-Myc Is a Critical Target for C/EBPα in Granulopoiesis". Molecular and Cellular Biology 21, № 11 (2001): 3789–806. http://dx.doi.org/10.1128/mcb.21.11.3789-3806.2001.

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ABSTRACT CCAAT/enhancer binding protein α (C/EBPα) is an integral factor in the granulocytic developmental pathway, as myeloblasts from C/EBPα-null mice exhibit an early block in differentiation. Since mice deficient for known C/EBPα target genes do not exhibit the same block in granulocyte maturation, we sought to identify additional C/EBPα target genes essential for myeloid cell development. To identify such genes, we used both representational difference analysis and oligonucleotide array analysis with RNA derived from a C/EBPα-inducible myeloid cell line. From each of these independent screens, we identified c-Myc as a C/EBPα negatively regulated gene. We mapped an E2F binding site in the c-Myc promoter as thecis-acting element critical for C/EBPα negative regulation. The identification of c-Myc as a C/EBPα target gene is intriguing, as it has been previously shown that down-regulation of c-Myc can induce myeloid differentiation. Here we show that stable expression of c-Myc from an exogenous promoter not responsive to C/EBPα-mediated down-regulation forces myeloblasts to remain in an undifferentiated state. Therefore, C/EBPα negative regulation of c-Myc is critical for allowing early myeloid precursors to enter a differentiation pathway. This is the first report to demonstrate that C/EBPα directly affects the level of c-Myc expression and, thus, the decision of myeloid blasts to enter into the granulocytic differentiation pathway.
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14

Cowling, Victoria H., and Michael D. Cole. "The Myc Transactivation Domain Promotes Global Phosphorylation of the RNA Polymerase II Carboxy-Terminal Domain Independently of Direct DNA Binding." Molecular and Cellular Biology 27, no. 6 (2007): 2059–73. http://dx.doi.org/10.1128/mcb.01828-06.

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ABSTRACT Myc is a transcription factor which is dependent on its DNA binding domain for transcriptional regulation of target genes. Here, we report the surprising finding that Myc mutants devoid of direct DNA binding activity and Myc target gene regulation can rescue a substantial fraction of the growth defect in myc −/− fibroblasts. Expression of the Myc transactivation domain alone induces a transcription-independent elevation of the RNA polymerase II (Pol II) C-terminal domain (CTD) kinases cyclin-dependent kinase 7 (CDK7) and CDK9 and a global increase in CTD phosphorylation. The Myc transactivation domain binds to the transcription initiation sites of these promoters and stimulates TFIIH binding in an MBII-dependent manner. Expression of the Myc transactivation domain increases CDK mRNA cap methylation, polysome loading, and the rate of translation. We find that some traditional Myc transcriptional target genes are also regulated by this Myc-driven translation mechanism. We propose that Myc transactivation domain-driven RNA Pol II CTD phosphorylation has broad effects on both transcription and mRNA metabolism.
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15

Chatterjee, Bishwanath, Salah Boudjadi, Puspa Raj Pandey, Hana Kim, Wenyue Sun, and Frederic G. Barr. "Abstract 3536: Role of Myc family proteins in fusion-positive rhabdomyosarcoma." Cancer Research 83, no. 7_Supplement (2023): 3536. http://dx.doi.org/10.1158/1538-7445.am2023-3536.

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Abstract Fusion-positive rhabdomyosarcoma (FP RMS) is an aggressive pediatric malignancy characterized by the presence of a PAX3-FOXO1 (P3F) or PAX7-FOXO1 fusion gene. Previous RNA expression studies have shown that these FP RMS tumors also express high levels of MYCN and lower levels of MYC. Our recent studies of FP RMS tumors revealed an inverse relationship between MYCN and MYC RNA expression in FP RMS tumors. Western blot studies of FP RMS cell lines and patient-derived xenograft (PDX) tumors identified tumors with high level MYCN and MYC protein expression as well as tumors with high level protein expression of either MYC or MYCN. To model the interaction of P3F with Myc family proteins in FP RMS, we generated human Dbt myoblasts with doxycycline-inducible P3F (iP3F) with or without constitutively expressed MYCN. We previously observed that doxycycline-treated human Dbt myoblasts engineered with iP3F and constitutive MYCN expression (Dbt-MYCN-iP3F) form foci in vitro and rapidly form tumors in vivo, while doxycycline-treated Dbt myoblasts engineered with only iP3F expression (Dbt-iP3F) do not form foci in vitro and form tumors in vivo at a slower rate. Western blot and qRT-PCR analysis of the parental and tumor-derived (TD) Dbt-MYCN-iP3F lines revealed high MYCN and low MYC expression. In contrast, Dbt-iP3F parental lines express moderate levels of MYC and very low levels of MYCN whereas iP3F TD lines show increased MYC and MYCN expression, though this level of MYCN expression is considerably less than that seen in Dbt-MYCN-iP3F lines. Using CRISPR-Cas9 technology to knockdown MYCN or MYC, we found a primary dependence on MYCN in both Dbt-MYCN-iP3F parental and TD lines as indicated by loss of focus formation following MYCN knockdown while MYC knockdown does not interfere with oncogenicity. In contrast, oncogenicity in Dbt-iP3F TD lines is primarily dependent upon MYC whereas MYCN knockdown results in a modest and variable effect on oncogenicity. To elucidate the role of Myc proteins on the expression of P3F target genes, we measured expression of several transcriptional targets in these parental and TD lines by RNA sequencing and qRT-PCR. Several target genes (such as FGFR4) showed comparable upregulation by P3F in both parental and TD lines with or without constitutive MYCN expression. In contrast, a few target genes (such as FGF8) were stimulated by P3F at low levels in Dbt-iP3F parental lines and were stimulated at much higher levels in Dbt-iP3F TD lines as well as in both Dbt-MYCN-iP3F parental and TD lines. This finding indicates that some P3F target genes do not require high MYCN or MYC expression whereas other P3F target genes can only be maximally stimulated by P3F in the presence of high levels of MYCN and/or MYC. We postulate that the dependence of FP RMS on high level expression of a Myc family protein may be explained by the need to stimulate expression of one or more of the P3F target genes in this latter category. Citation Format: Bishwanath Chatterjee, Salah Boudjadi, Puspa Raj Pandey, Hana Kim, Wenyue Sun, Frederic G. Barr. Role of Myc family proteins in fusion-positive rhabdomyosarcoma. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3536.
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Yang, Zhenhua, Kushani Shah, Jonathan Augustin, Jing Hu, and Hao Jiang. "Role of the Dpy30 Subunit of Set1/Mll Complexes in Lymphomagenesis through Epigenetic Regulation of Myc Activity." Blood 126, no. 23 (2015): 310. http://dx.doi.org/10.1182/blood.v126.23.310.310.

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Abstract Epigenetic modulators have emerged as promising targets for treating cancers, especially blood cancers. As the major histone H3K4 methylation enzymes in mammals, the SET1/MLL complexes represent potential drug targets in epigenetic therapeutics due to (i) the intimate connection of H3K4 methylation with gene expression, and (ii) their extensive association with multiple cancers including blood cancers. However, the functional role for the SET1/MLL complexes in tumorigenesis remains largely unclear. The SET1/MLL complexes comprise one of six different catalytic subunits and several shared core subunits including DPY30. We have previously shown that DPY30 directly facilitates genome-wide H3K4 methylation, and plays a crucial role in fundamental cellular processes including proliferation and differentiation, especially in the hematopoietic system. Our new analyses have shown that the core, but not the catalytic, subunits of SET1/MLL complexes is significantly up-regulated in primary human Burkitt's lymphomas bearing MYC-Ig translocations compared to other B lymphomas, and Myc binds to genes encoding the core but not the catalytic subunits. These results indicate that the core subunits are directly regulated by MYC, and prompted us to study their functional role in MYC-driven tumorigenesis. Using a Dpy30 conditional knockout mouse model that we recently established, we have shown a critical role of Dpy30 in the fate determination of hematopoietic stem and progenitor cells. Due to the severe pancytopenia of the knockout mice, we tested if genetically reducing Dpy30 dose may affect Myc-driven tumorigenesis in the Eμ-myc mouse. We found that Eμ-myc; Dpy30+/- mice survived significantly longer than their Eμ-myc littermates (see figure), with the median survival extended from 121 to 180 days, and with significantly alleviated spleen enlargement. Importantly, Dpy30+/- mice (no Eμ-myc) appear completely healthy with normal blood profiles. These results demonstrate that reducing Dpy30 level confers a significant resistance to Myc-driven lymphomagenesis without affecting normal physiology. We then found that, in the presence of Eμ -Myc, Dpy30 heterozygosity significantly increased apoptosis of splenic B cells, and reduced expression of some key anti-apoptotic genes. We further showed that Dpy30 directly bound to and controlled the H3K4 methylation at the regulated anti-apoptosis genes in splenic B cells. These results suggest that Myc overexpression increases the dependence of key apoptosis-regulatory genes on Dpy30, and thus sensitizes tumor cells to Dpy30 inhibition, exhibiting "epigenetic vulnerability". To further study DPY30's role in MYC-dependent tumorigenesis at the molecular level, we have shown that DPY30 depletion in a MYC-dependent B lymphoma cell line markedly reduced (i) the lymphoma cell growth, (ii) expression of MYC targets, and most interestingly, (iii) binding of MYC to many of its genomic targets, as revealed by our ChIP-seq results. These results suggest that, in addition to promoting the expression of MYC gene itself that we previously found, DPY30 also reguates MYC's activity through promoting the genomic binding of MYC protein for target transcription. Taken together, our studies have established an important role of Dpy30 in the Myc-driven lymphomagenesis, partially through its regulation of the target binding activity of Myc. Further studies of the genome-wide impact of Dpy30 inhibition on the chromatin configuration and expression of key tumoregenic genes are undergoing and will be discussed. These studies will help us understand how Dpy30-mediated chromatin modification coordinates with key oncogenes in promoting hematological malignancies, and thus may represent a potential epigenetic target in treatment of certain blood cancers. Figure 1. Figure 1. Disclosures No relevant conflicts of interest to declare.
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Catic, Andre, Laure Maneix, Polina Iakova, et al. "Epigenetic Silencing of MYC By Proteasome Inhibitors." Blood 138, Supplement 1 (2021): 2212. http://dx.doi.org/10.1182/blood-2021-151315.

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Abstract Proteasome inhibitors were first introduced to the clinic almost 20 years ago and have since become standard of care in multiple myeloma treatment, a cancer of terminally differentiated plasma cells. The proteasome degrades most cellular proteins and identifies targets following ubiquitination by an elaborate enzymatic cascade. Blocking the turnover of proteins with proteasome inhibitors affects many pathways, including signaling, metabolism, and stress responses. Transcriptional and epigenetic regulators are short-lived proteins, and proteasome inhibition is expected to alter gene activity dramatically. However, some of the least understood aspects of proteasome inhibitors involve their effects on epigenetics and transcription. One reason for this knowledge gap is the technical challenge of distinguishing the direct from indirect effects of proteasome inhibition on transcription. To overcome this limitation, we developed an approach to map the nuclear location of protein turnover. We detected MYC target genes as a prevalent site of proteasomal protein degradation in multiple myeloma cells. Multiple myeloma is addicted to the proto-oncogene MYC, and several new approaches are being tested to silence MYC in this cancer. MYC is a short-lived protein, and proteasome inhibitors should stabilize MYC. However, with increased MYC levels, it is unclear why proteasome inhibition would be clinically beneficial. Instead, we found that proteasome inhibition reduces the levels of MYC and the activity of its target genes. The surprising reduction of MYC by proteasome inhibitors makes sense given their clinical effect. To identify the molecular mechanism by which proteasome inhibitors suppress MYC, we performed an integrative genomic analysis on the effects of these drugs and found that MYC is silenced at the transcriptional level by epigenetic suppression of its super-enhancer. We found that acetylated H3K27, a histone modification that increases the accessibility of chromatin and facilitates transcription, is rapidly lost upon proteasome inhibition. We hypothesized that this is caused by the stabilization of a histone deacetylase (HDAC). Based on data from the APEX study, we discovered that HDAC3 antagonizes the activity of MYC, and cancers with high HDAC3 expression correlate with better outcomes. Indeed, we found that proteasome inhibition locally increases HDAC3 levels at target promoters and the MYC super-enhancer and that genetic depletion of HDAC3 reduces the epigenetic effects of proteasome inhibition. In addition to its epigenetic role, HDAC3 has recently been shown to repress genes by disrupting their location. In agreement with these findings, we discovered that target genes relocate into heterochromatin-rich lamina-associated areas of the nucleus upon proteasome inhibition. These results suggest that HDAC3 might also act as a suppressor of MYC in a manner that does not require catalytic deacetylase activity. Such a repressive function would, therefore, not be targeted by HDAC inhibitors. In summary, our study supports a new role of proteasome inhibitors as antagonists of the proto-oncogene MYC. The drugs accomplish this effect by stabilizing HDAC3 at the MYC super-enhancer and MYC target genes. As a consequence, elevated HDAC3 represses chromatin epigenetically and possibly alters the nuclear architecture by relocating chromosomes. These findings are surprising as they point towards a novel mechanism to limit MYC, which is dysregulated in 70% of cancers. Our results may also explain why some highly MYC-addicted cancers have a particular sensitivity towards proteasome inhibitors. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.
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Clurman, B. E., and W. S. Hayward. "Multiple proto-oncogene activations in avian leukosis virus-induced lymphomas: evidence for stage-specific events." Molecular and Cellular Biology 9, no. 6 (1989): 2657–64. http://dx.doi.org/10.1128/mcb.9.6.2657-2664.1989.

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We have examined avian leukosis virus-induced B-cell lymphomas for multiple, stage-specific oncogene activations. Three targets for viral integration were identified: c-myb, c-myc, and a newly identified locus termed c-bic. The c-myb and c-myc genes were associated with different lymphoma phenotypes. The c-bic locus was a target for integration in one class of lymphomas, usually in conjunction with c-myc activation. The data indicate that c-myc and c-bic may act synergistically during lymphomagenesis and that c-bic is involved in late stages of tumor progression.
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Clurman, B. E., and W. S. Hayward. "Multiple proto-oncogene activations in avian leukosis virus-induced lymphomas: evidence for stage-specific events." Molecular and Cellular Biology 9, no. 6 (1989): 2657–64. http://dx.doi.org/10.1128/mcb.9.6.2657.

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We have examined avian leukosis virus-induced B-cell lymphomas for multiple, stage-specific oncogene activations. Three targets for viral integration were identified: c-myb, c-myc, and a newly identified locus termed c-bic. The c-myb and c-myc genes were associated with different lymphoma phenotypes. The c-bic locus was a target for integration in one class of lymphomas, usually in conjunction with c-myc activation. The data indicate that c-myc and c-bic may act synergistically during lymphomagenesis and that c-bic is involved in late stages of tumor progression.
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Nilsson, Jonas A., Kirsteen H. Maclean, Ulrich B. Keller, Helene Pendeville, Troy A. Baudino, and John L. Cleveland. "Mnt Loss Triggers Myc Transcription Targets, Proliferation, Apoptosis, and Transformation." Molecular and Cellular Biology 24, no. 4 (2004): 1560–69. http://dx.doi.org/10.1128/mcb.24.4.1560-1569.2004.

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ABSTRACT Myc oncoproteins are overexpressed in most cancers and are sufficient to accelerate cell proliferation and provoke transformation. However, in normal cells Myc also triggers apoptosis. All of the effects of Myc require its function as a transcription factor that dimerizes with Max. This complex induces genes containing CACGTG E-boxes, such as Ornithine decarboxylase (Odc), which harbors two of these elements. Here we report that in quiescent cells the Odc E-boxes are occupied by Max and Mnt, a putative Myc antagonist, and that this complex is displaced by Myc-Max complexes in proliferating cells. Knockdown of Mnt expression by stable retroviral RNA interference triggers many targets typical of the “Myc” response and provokes accelerated proliferation and apoptosis. Strikingly, these effects of Mnt knockdown are even manifest in cells lacking c-myc. Moreover, Mnt knockdown is sufficient to transform primary fibroblasts in conjunction with Ras. Therefore, Mnt behaves as a tumor suppressor. These findings support a model where Mnt represses Myc target genes and Myc functions as an oncogene by relieving Mnt-mediated repression.
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O'Donnell, Kathryn A., Duonan Yu, Karen I. Zeller, et al. "Activation of Transferrin Receptor 1 by c-Myc Enhances Cellular Proliferation and Tumorigenesis." Molecular and Cellular Biology 26, no. 6 (2006): 2373–86. http://dx.doi.org/10.1128/mcb.26.6.2373-2386.2006.

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ABSTRACT Overexpression of transferrin receptor 1 (TFRC1), a major mediator of iron uptake in mammalian cells, is a common feature of human malignancies. Therapeutic strategies designed to interfere with tumor iron metabolism have targeted TFRC1. The c-Myc oncogenic transcription factor stimulates proliferation and growth by activating thousands of target genes. Here we demonstrate that TFRC1 is a critical downstream target of c-Myc. Using in vitro and in vivo models of B-cell lymphoma, we show that TFRC1 expression is activated by c-Myc. Chromatin immunoprecipitation experiments reveal that c-Myc directly binds a conserved region of TFRC1. In light of these findings, we sought to determine whether TFRC1 is required for c-Myc-mediated cellular proliferation and cell size control. TFRC1 inhibition decreases cellular proliferation and results in G1 arrest without affecting cell size. Consistent with these findings, expression profiling reveals that TFRC1 depletion alters expression of genes that regulate the cell cycle. Furthermore, enforced TFRC1 expression confers a growth advantage to cells and significantly enhances the rate of c-Myc-mediated tumor formation in vivo. These findings provide a molecular basis for increased TFRC1 expression in human tumors, illuminate the role of TFRC1 in the c-Myc target gene network, and support strategies that target TFRC1 for cancer therapy.
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22

Pandolfi, Ashley, Robert F. Stanley, Yiting Yu, et al. "PAK1 is a therapeutic target in acute myeloid leukemia and myelodysplastic syndrome." Blood 126, no. 9 (2015): 1118–27. http://dx.doi.org/10.1182/blood-2014-12-618801.

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Key Points Targeting of PAK1 inhibits primary AML and MDS patients' cells including leukemia stem cells but spares healthy stem and progenitor cells. Inhibition of PAK1 induces differentiation and apoptosis of AML cells through downregulation of MYC and a core network of MYC target genes.
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23

Yeilding, N. M., and W. M. Lee. "Coding elements in exons 2 and 3 target c-myc mRNA downregulation during myogenic differentiation." Molecular and Cellular Biology 17, no. 5 (1997): 2698–707. http://dx.doi.org/10.1128/mcb.17.5.2698.

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Downregulation in expression of the c-myc proto-oncogene is an early molecular event in differentiation of murine C2C12 myoblasts into multinucleated myotubes. During differentiation, levels of c-myc mRNA decrease 3- to 10-fold despite a lack of change in its transcription rate. To identify cis-acting elements that target c-myc mRNA for downregulation during myogenesis, we stably transfected C2C12 cells with mutant myc genes or chimeric genes in which various myc sequences were fused to the human beta-globin gene or to the bacterial chloramphenicol acetyltransferase (CAT) gene. Deletion of coding sequences from myc exon 2 or exon 3 abolished downregulation of myc mRNA during myogenic differentiation, while deletion of introns or sequences in the 5' or 3' untranslated regions (UTRs) did not, demonstrating that coding elements in both exons 2 and 3 are necessary for myc mRNA downregulation. Fusion of coding sequences from either myc exon 2 or 3 to beta-globin mRNA conferred downregulation onto the chimeric mRNA, while fusion of myc 3' UTR sequences or coding sequences from CAT or ribosomal protein L32 did not, demonstrating that coding elements in myc exons 2 and 3 specifically confer downregulation. These results present the apparent paradox that coding elements in either myc exon 2 or myc exon 3 are sufficient to confer downregulation onto beta-globin mRNA, but neither element alone was sufficient for myc mRNA downregulation, suggesting that some feature of beta-globin mRNA may potentiate the regulatory properties of myc exons 2 and 3. A similar regulatory function is not shared by all mRNAs because fusion of either myc exon 2 or myc exon 3 to CAT mRNA did not confer downregulation onto the chimeric mRNA, but fusion of the two elements together did. We conclude from these results that two myc regulatory elements, one exon 2 and one in exon 3, are required for myc mRNA downregulation. Finally, using a highly sensitive and specific PCR-based assay for comparing mRNA levels, we demonstrated that the downregulation mediated by myc exons 2 and 3 results in a decrease in cytoplasmic mRNA levels, but not nuclear mRNA levels, indicating that regulation is a postnuclear event.
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Zhuang, Zhenjie, Qianying Chen, Cihui Huang, Junmao Wen, Haifu Huang, and Zhanhua Liu. "A Comprehensive Network Pharmacology-Based Strategy to Investigate Multiple Mechanisms of HeChan Tablet on Lung Cancer." Evidence-Based Complementary and Alternative Medicine 2020 (May 30, 2020): 1–17. http://dx.doi.org/10.1155/2020/7658342.

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Background. HeChan tablet (HCT) is a traditional Chinese medicine preparation extensively prescribed to treat lung cancer in China. However, the pharmacological mechanisms of HCT on lung cancer remain to be elucidated. Methods. A comprehensive network pharmacology-based strategy was conducted to explore underlying mechanisms of HCT on lung cancer. Putative targets and compounds of HCT were retrieved from TCMSP and BATMAN-TCM databases; related genes of lung cancer were retrieved from OMIM and DisGeNET databases; known therapeutic target genes of lung cancer were retrieved from TTD and DrugBank databases; PPI networks among target genes were constructed to filter hub genes by STRING. Furthermore, the pathway and GO enrichment analysis of hub genes was performed by clusterProfiler, and the clinical significance of hub genes was identified by The Cancer Genome Atlas. Result. A total of 206 compounds and 2,433 target genes of HCT were obtained. 5,317 related genes of lung cancer and 77 known therapeutic target genes of lung cancer were identified. 507 unique target genes were identified among HCT-related genes of lung cancer and 34 unique target genes were identified among HCT-known therapeutic target genes of lung cancer. By PPI networks, 11 target genes AKT1, TP53, MAPK8, JUN, EGFR, TNF, INS, IL-6, MYC, VEGFA, and MAPK1 were identified as major hub genes. IL-6, JUN, EGFR, and MYC were shown to associate with the survival of lung cancer patients. Five compounds of HCT, quercetin, luteolin, kaempferol, beta-sitosterol, and baicalein were recognized as key compounds of HCT on lung cancer. The gene enrichment analysis implied that HCT probably benefitted patients with lung cancer by modulating the MAPK and PI3K-Akt pathways. Conclusion. This study predicted pharmacological and molecular mechanisms of HCT against lung cancer and could pave the way for further experimental research and clinical application of HCT.
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Nikiforov, Mikhail A., Sanjay Chandriani, Brenda O'Connell, et al. "A Functional Screen for Myc-Responsive Genes Reveals Serine Hydroxymethyltransferase, a Major Source of the One-Carbon Unit for Cell Metabolism." Molecular and Cellular Biology 22, no. 16 (2002): 5793–800. http://dx.doi.org/10.1128/mcb.22.16.5793-5800.2002.

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ABSTRACT A cDNA library enriched with Myc-responsive cDNAs but depleted of myc cDNAs was used in a functional screen for growth enhancement in c-myc-null cells. A cDNA clone for mitochondrial serine hydroxymethyltransferase (mSHMT) that was capable of partial complementation of the growth defects of c-myc-null cells was identified. Expression analysis and chromatin immunoprecipitation demonstrated that mSHMT is a direct Myc target gene. Furthermore, a separate gene encoding the cytoplasmic isoform of the same enzyme is also a direct target of Myc regulation. SHMT enzymes are the major source of the one-carbon unit required for folate metabolism and for the biosynthesis of nucleotides and amino acids. Our data establish a novel functional link between Myc and the regulation of cellular metabolism.
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26

Prochownik, Edward V., and Huabo Wang. "Normal and Neoplastic Growth Suppression by the Extended Myc Network." Cells 11, no. 4 (2022): 747. http://dx.doi.org/10.3390/cells11040747.

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Among the first discovered and most prominent cellular oncogenes is MYC, which encodes a bHLH-ZIP transcription factor (Myc) that both activates and suppresses numerous genes involved in proliferation, energy production, metabolism and translation. Myc belongs to a small group of bHLH-ZIP transcriptional regulators (the Myc Network) that includes its obligate heterodimerization partner Max and six “Mxd proteins” (Mxd1–4, Mnt and Mga), each of which heterodimerizes with Max and largely opposes Myc’s functions. More recently, a second group of bHLH-ZIP proteins (the Mlx Network) has emerged that bears many parallels with the Myc Network. It is comprised of the Myc-like factors ChREBP and MondoA, which, in association with the Max-like member Mlx, regulate smaller and more functionally restricted repertoires of target genes, some of which are shared with Myc. Opposing ChREBP and MondoA are heterodimers comprised of Mlx and Mxd1, Mxd4 and Mnt, which also structurally and operationally link the two Networks. We discuss here the functions of these “Extended Myc Network” members, with particular emphasis on their roles in suppressing normal and neoplastic growth. These roles are complex due to the temporal- and tissue-restricted expression of Extended Myc Network proteins in normal cells, their regulation of both common and unique target genes and, in some cases, their functional redundancy.
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Mahani, Amir, Gustav Arvidsson, Laia Sadeghi, Alf Grandien, and Anthony P. H. Wright. "Differential Transcriptional Reprogramming by Wild Type and Lymphoma-Associated Mutant MYC Proteins as B-Cells Convert to a Lymphoma Phenotype." Cancers 13, no. 23 (2021): 6093. http://dx.doi.org/10.3390/cancers13236093.

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The MYC transcription factor regulates a vast number of genes and is implicated in many human malignancies. In some hematological malignancies, MYC is frequently subject to missense mutations that enhance its transformation activity. Here, we use a novel murine cell system to (i) characterize the transcriptional effects of progressively increasing MYC levels as normal primary B-cells transform to lymphoma cells and (ii) determine how this gene regulation program is modified by lymphoma-associated MYC mutations (T58A and T58I) that enhance its transformation activity. Unlike many previous studies, the cell system exploits primary B-cells that are transduced to allow regulated MYC expression under circumstances where apoptosis and senescence pathways are abrogated by the over-expression of the Bcl-xL and BMI1 proteins. In such cells, transition from a normal to a lymphoma phenotype is directly dependent on the MYC expression level, without a requirement for secondary events that are normally required during MYC-driven oncogenic transformation. A generalized linear model approach allowed an integrated analysis of RNA sequencing data to identify regulated genes in relation to both progressively increasing MYC level and wild type or mutant status. Using this design, a total of 7569 regulated genes were identified, of which the majority (n = 7263) were regulated in response to progressively increased levels of wild type MYC, while a smaller number of genes (n = 917) were differentially regulated, compared to wild type MYC, in T58A MYC- and/or T58I MYC-expressing cells. Unlike most genes that are similarly regulated by both wild type and mutant MYC genes, the set of 917 genes did not significantly overlap with known lipopolysaccharide regulated genes, which represent genes regulated by MYC in normal B cells. The genes that were differently regulated in cells expressing mutant MYC proteins were significantly enriched in DNA replication and G2 phase to mitosis transition genes. Thus, mutants affecting MYC proteins may augment quantitative oncogenic effects on the expression of normal MYC-target genes with qualitative oncogenic effects, by which sets of cell cycle genes are abnormally targeted by MYC as B cells transition into lymphoma cells. The T58A and T58I mutations augment MYC-driven transformation by distinct mechanisms.
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Poole, Candace, Wenli Zheng, Haesung Lee, et al. "Targeting the MYC Oncogene in Burkitt Lymphoma through HSP90 Inhibition." Cancers 10, no. 11 (2018): 448. http://dx.doi.org/10.3390/cancers10110448.

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Overexpression of the MYC oncogene is a key feature of many human malignancies including Burkitt lymphoma. While MYC is widely regarded to be a promising therapeutic target, a clinically effective MYC inhibitor is still elusive. Here, we report an alternative strategy, targeting MYC indirectly through inhibition of the HSP90 machinery. We found that inhibition of HSP90 function reduces MYC expression in human Burkitt lymphoma through suppression of MYC transcription and destabilization of MYC protein, thereby diminishing the proliferation of tumor cells. Consistently, treatment of Burkitt lymphoma cell lines with HSP90 inhibitors (17-AAG or 17-DMAG) was accompanied by downregulation of canonical MYC target genes. Combination treatment with 17-DMAG and the proteasome inhibitor, MG-132, led to accumulation of MYC protein, indicating that upon HSP90 inhibition, MYC is degraded by the proteasome. Using co-immunoprecipitation, we furthermore demonstrated a direct interaction between MYC and HSP90, indicating that MYC is an HSP90 client protein in Burkitt lymphoma. Together, we report here the use of HSP90 inhibitors as an alternative approach to target the MYC oncogene and its network in Burkitt lymphoma.
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29

Da Silva, Fabio Pacheco Estumano. "Mapping Scientific and Technological Production Related to the MYC Gene." Revista Gestão Inovação e Tecnologias 11, no. 4 (2021): 5897–908. http://dx.doi.org/10.47059/revistageintec.v11i4.2647.

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In appropriate activation of c-MYC proto-oncogene contributes to the development of human cancers. Searches for therapies that target genes and proteins related to neoplastic phenotypes have become frequent. Therefore, inhibiting c-MYC expression has been the target for developing and testing multiple drugs and strategies for the treatment of various human cancers. This study aimed to map scientific and technological productions on the MYC gene at the Scielo, PubMed and Orbit Intelligence platforms between 2000 and 2019. The scientific prospecting revealed 1,259 articles. The most detected categories were: molecular biology, MYC mutations and those addressing the MYC as a drug target or therapeutic strategies. A progressive increase in the number of articles in this last category was found. Technological mapping detected 10,059 patent documents, with 20.2% granted. China and the USA were the largest filers, accounting for more than 40%. Biotechnology was the field with the highest number of patents. Biotechnology and the pharmaceutical sector predominated in the second half of the period investigated, both in scientific and technological prospecting. Our study points to a scientific and technological effort in the development of therapeutic strategies against cancer, in which MYC is among the main targets.
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Kim, H. K., I. J. Choi, C. G. Kim, A. Oshima, and J. E. Green. "Gene expression signatures to predict the response of gastric cancer to cisplatin and fluorouracil." Journal of Clinical Oncology 27, no. 15_suppl (2009): 4628. http://dx.doi.org/10.1200/jco.2009.27.15_suppl.4628.

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4628 Background: A prospective high-throughput gene expression study was conducted to identify transcriptional profiles predictive of a clinical response to cisplatin and fluorouracil (CF) combination chemotherapy and to identify dysregulated genes associated with acquired resistance to CF. Methods: Endoscopic biopsy samples were collected from CF-treated metastatic gastric cancer (MGC) patients (pts) prior to CF (n = 123) and following the development of resistance (n = 22) at the National Cancer Center of Korea from 2001 to 2006, and analyzed using CGH and expression microarrays. We developed 2 survival risk predictors. The first predictor was constructed using genes in DNA amplicons and identified in the expression signature that correlates with survival (intrinsic resistance signature). The second predictor was based on the acquired resistance signature, which was identified by comparing matched expression array data from initially responsive patients prior to treatment with profiles obtained at progressive disease. Results: Array CGH revealed the gene amplification of MYC, EGFR, and FGFR2 whose Affymetrix U133A signals significantly correlated with a poor prognosis (P values, 0.0154, 0.0096, and 0.0057) of training set pts (n = 96). Three-gene-predicted high-risk group of the validation cohort (n = 10) demonstrated a shorter median survival than low-risk (n = 17) group (7.4 vs 16.8 months; p = 0.047). The 3-gene signature, as a continuous variable, was the independent predictor for overall survival (OS) and time to progression (TTP) (adjusted P, 0.021, and 0.012). Importantly, the acquired resistance signature strongly overlapped the intrinsic resistance signature (LS P<10-5), and was highly enriched for MYC target genes (LS p = 2x10-5). A predictor based on MYC target genes within the acquired resistance signature was the independent predictor for OS and TTP of 101 separate pts (adjusted p, 0.015, and 0.011). Conclusions: Combined overexpression of MYC, EGFR, and FGFR2 predicts a poor response of MGC pts to CF. There is significant overlap between intrinsic and acquired resistance signatures of MGC, where the MYC gene network plays a central role. This is the first demonstration that the acquired resistance signature predicts the initial response to chemotherapy. No significant financial relationships to disclose.
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Cowling, Victoria H., Celina M. D'Cruz, Lewis A. Chodosh, and Michael D. Cole. "c-Myc Transforms Human Mammary Epithelial Cells through Repression of the Wnt Inhibitors DKK1 and SFRP1." Molecular and Cellular Biology 27, no. 14 (2007): 5135–46. http://dx.doi.org/10.1128/mcb.02282-06.

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ABSTRACT c-myc is frequently amplified in breast cancer; however, the mechanism of myc-induced mammary epithelial cell transformation has not been defined. We show that c-Myc induces a profound morphological transformation in human mammary epithelial cells and anchorage-independent growth. c-Myc suppresses the Wnt inhibitors DKK1 and SFRP1, and derepression of DKK1 or SFRP1 reduces Myc-dependent transforming activity. Myc-dependent repression of DKK1 and SFRP1 is accompanied by Wnt target gene activation and endogenous T-cell factor activity. Myc-induced mouse mammary tumors have repressed SFRP1 and increased expression of Wnt target genes. DKK1 and SFRP1 inhibit the transformed phenotype of breast cancer cell lines, and DKK1 inhibits tumor formation. We propose a positive feedback loop for activation of the c-myc and Wnt pathways in breast cancer.
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32

Fog, Cathrine Kolster, Fazila Asmar, Christophe Côme, et al. "Loss of PRDM11 promotes MYC-driven lymphomagenesis." Blood 125, no. 8 (2015): 1272–81. http://dx.doi.org/10.1182/blood-2014-03-560805.

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33

Desterke, Christophe, Patricia Hugues, Jin Wook Hwang, Annelise Bennaceur-Griscelli, and Ali G. Turhan. "Embryonic Program Activated during Blast Crisis of Chronic Myelogenous Leukemia (CML) Implicates a TCF7L2 and MYC Cooperative Chromatin Binding." International Journal of Molecular Sciences 21, no. 11 (2020): 4057. http://dx.doi.org/10.3390/ijms21114057.

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Chronic myeloid leukemia (CML) is characterized by an inherent genetic instability, which contributes to the progression of the disease towards an accelerated phase (AP) and blast crisis (BC). Several cytogenetic and genomic alterations have been reported in the progression towards BC, but the precise molecular mechanisms of this event are undetermined. Transcription Factor 7 like 2 (TFC7L2) is a member of the TCF family of proteins that are known to activate WNT target genes such as Cyclin D1. TCF7L2 has been shown to be overexpressed in acute myeloid leukemia (AML) and represents a druggable target. We report here that TCF7L2 transcription factor expression was found to be correlated to blast cell numbers during the progression of the disease. In these cells, TCF7L2 CHIP-sequencing highlighted distal cis active enhancer, such as elements in SMAD3, ATF5, and PRMT1 genomic regions and a proximal active transcriptional program of 144 genes. The analysis of CHIP-sequencing of MYC revealed a significant overlapping of TCF7L2 epigenetic program with MYC. The β-catenin activator lithium chloride and the MYC-MAX dimerization inhibitor 10058-F4 significantly modified the expression of three epigenetic targets in the BC cell line K562. These results suggest for the first time the cooperative role of TCF7L2 and MYC during CML-BC and they strengthen previous data showing a possible involvement of embryonic genes in this process.
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Licenziato, Luca, Eugenio Mazzone, Chiara Tarantelli, et al. "Thinking Outside the Box: Indirect Myc Modulation in Canine B-Cell Lymphoma." Animals 14, no. 10 (2024): 1466. http://dx.doi.org/10.3390/ani14101466.

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B-cell lymphomas (BCL) is the most frequent hematological cancer in dogs. Treatment typically consists of chemotherapy, with CHOP-based protocols. However, outcome remains generally poor, urging the exploration of new therapeutic strategies with a targeted approach. Myc transcription factor plays a crucial role in regulating cellular processes, and its dysregulation is implicated in numerous human and canine malignancies, including canine BCL (cBCL). This study aims to evaluate the efficacy of indirectly inhibiting Myc in cBCL using BI2536 and MZ1 compounds in two in vitro models (CLBL-1 and KLR-1201). Both BI2536 and MZ1, alone and combined, affected cell viability in a significant concentration- and time-dependent manner. Western Blot revealed an upregulation of PLK1 expression in both cell lines upon treatment with BI2536, in association with a reduction in c-Myc protein levels. Conversely, MZ1 led to a decrease in its primary target, BRD4, along with a reduction in c-Myc. Furthermore, BI2536, both alone and in combination with MZ1, induced larger transcriptomic changes in cells compared to MZ1 alone, primarily affecting MYC target genes and genes involved in cell cycle regulation. These data underscore the potential role of Myc as therapeutic target in cBCL, providing a novel approach to indirectly modulate this molecule.
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35

Rothermund, Krisiti, Kenneth Rogulski, Elaine Fernandes, et al. "C-Myc–Independent Restoration of Multiple Phenotypes by Two C-Myc Target Genes with Overlapping Functions." Cancer Research 65, no. 6 (2005): 2097–107. http://dx.doi.org/10.1158/0008-5472.can-04-2928.

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36

Chen, Yili, Thomas W. Blackwell, Jing Gao, et al. "Computational Prediction of c-MYC Binding and Action by Integration of Multiple Data Sources." Blood 108, no. 11 (2006): 4345. http://dx.doi.org/10.1182/blood.v108.11.4345.4345.

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Abstract c-MYC is an important proto-oncogene. Its actions are mediated by sequence specific binding of the c-MYC protein to genomic DNA. While many c-MYC recognition sites can be identified in c-MYC responsive genes, many others are associated with genes showing no c-MYC response. It is not yet known how the cell determines which of the many c-MYC recognition sites are biologically active and directly bind c-MYC protein to regulate gene expression. We have developed a computational model that predict c-MYC binding and functional activation as distinct processes. Our model integrates four types of evidence to predict functional c-MYC targets: genomic sequence, MYC binding, gene expression and gene function annotations. First, a Bayesian network classifier is used to predict c-MYC recognition sites likely to exhibit high occupancy binding in chromatin immunoprecipitation studies using several types of sequence information, including predicted DNA methylation using a computational model to estimate the likelihood of genomic DNA methylation. In the second step, the DNA binding probability of MYC is combined with the gene expression information from 9 independent microarray datasets in multiple tissues and the gene function annotations in Gene Ontology to predict the c-MYC targets. The prediction results were compared with the c-MYC targets in public MYC target database [www.myccancergene.org], which collected the c-MYC targets identified in biomedical literatures. In total, we predicted 599 likely c-MYC genes on human genome, of which 73 have been reported to be both bound and regulated by MYC, 83 are bound by MYC in vivo and another 93 are MYC regulated. The approach thus successfully identified many known c-MYC targets as well as suggesting many novel sites including many sites that are remote from the transcription start site. Our findings suggest that to identify c-MYC genomic targets, any study based on single high throughput dataset is likely to be insufficient. Using multiple gene expression datasets helps to improve the sensitivity and integration of different data sources helps to improve the specificity. Summary of c-MYC Targets Prediction Microarray Dataset Data Source (Citation) Tissue Predicted Targets Binding&Regulation Reported Only Binding Reported Only Regulation Reported 1 PMID: 15778709 B Cell 421 61 60 56 2 PMID: 12086878 Prostate Cancer 428 56 65 76 3 PMID: 14722351 Prostate Cancer 50 4 7 13 4 PMID: 15254046 Prostate Cancer 66 19 8 14 5 PMID: 12747878 Breast Cancer 17 1 3 5 6 PMID: 11707567 Lung Cancer 295 51 42 59 7 PMID: 15820940 CML 8 1 1 2 8 PMID: 12704389 ALL 222 45 32 46 9 PMID: 11731795 ALL / MLL / AML 22 6 1 6 Total 599 73 83 93
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Delpuech, Oona, Beatrice Griffiths, Philip East та ін. "Induction of Mxi1-SRα by FOXO3a Contributes to Repression of Myc-Dependent Gene Expression". Molecular and Cellular Biology 27, № 13 (2007): 4917–30. http://dx.doi.org/10.1128/mcb.01789-06.

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ABSTRACT Forkhead transcription factors of the O class (FOXOs) are important targets of the phosphatidylinositol 3-kinase (PI3-kinase)/Akt pathway. FOXOs have been implicated in the regulation of cell cycle progression, oxidative stress resistance, and apoptosis. Using DNA microarrays, we analyzed the transcriptional response to FOXO3a activation by gene expression analysis in DLD-1 colon cancer cells stably expressing a FOXO3a.A3-ER fusion protein. We found that activation of FOXO3a resulted in repression of a number of previously identified Myc target genes. Furthermore, FOXO3a activation induced expression of several members of the Mad/Mxd family of transcriptional repressors, most notably Mxi1. The induction of Mxi1 by FOXO3a was specific to the Mxi1-SRα isoform and was mediated by three highly conserved FOXO binding sites within the first intron of the gene. Activation of FOXO3a in response to inhibition of Akt also resulted in activation of Mxi1-SRα expression. Silencing of Mxi1 by small interfering RNA (siRNA) reduced FOXO3a-mediated repression of a number of Myc target genes. We also observed that FOXO3a activation induced a switch in promoter occupancy from Myc to Mxi1 on the E-box containing promoter regions of two Myc target genes, APEX and FOXM1. siRNA-mediated transient silencing of Mxi1 or all Mad/Mxd proteins reduced exit from S phase in response to FOXO3a activation, and stable silencing of Mxi1 or Mad1 reduced the growth inhibitory effect of FOXO3a. We conclude that induction of Mad/Mxd proteins contributes to the inhibition of proliferation in response to FOXO3a activation. Our results provide evidence of direct regulation of Mxi1 by FOXO3a and imply an additional mechanism through which the PI3-kinase/Akt/FOXO pathway can modulate Myc function.
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38

Cheng, Jing, and Lawrence P. Kane. "Global identification of genes and pathways regulated by Akt during activation of T helper cells." F1000Research 2 (April 15, 2013): 109. http://dx.doi.org/10.12688/f1000research.2-109.v1.

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We previously demonstrated that Akt differentially modulated a subset of NF-kB target genes during T cell activation. In the current study, we further explored the broader effects of Akt inhibition on T cell gene induction. Global microarray analysis was used to characterize T helper cell transcriptional responses following antigen receptor stimulation in the absence or presence of Akti1/2 (an allosteric inhibitor which targets Akt1 and Akt2), to identify novel targets dependent upon Akt and obtain a more comprehensive view of Akt-sensitive genes in T helper cells. Pathway analysis of microarray data from a CD4+ T cell line revealed effects on gene networks involving ribosomal and T cell receptor signaling pathways associated with Akti1/2 treatment. Using real-time PCR analysis, we validated differential regulation of several genes in these pathways, including Ier3, Il13, Klf6, Egr1, Ccl1 and Ccl4, among others. Additionally, transcription factor target gene (TFactS) analysis revealed that NF-kB and Myc were the most significantly enriched transcription factors among Akt-dependent genes after T cell receptor and CD28 stimulation. Akt activation elicited increases in the enrichment of NF-kB- and Myc-targeted genes. The present study has identified a diverse set of genes, and possible mechanisms for their regulation, that are dependent on Akt during T cell activation.
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39

Schmidt, Christin, Albertas Navickas, Frederique Zindy, et al. "OMIC-03. TRANSLATIONAL CONTROL IN MYC AND MYCN MEDULLOBLASTOMA." Neuro-Oncology 23, Supplement_1 (2021): i37. http://dx.doi.org/10.1093/neuonc/noab090.150.

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Abstract Medulloblastoma has been extensively characterized at the genomic and transcriptional levels, but little is known about how alterations in translational control underlie tumor development. Myc and Mycn are often deregulated in medulloblastoma and play important roles in tumor initiation, maintenance and progression. Although both proteins have similar structures and are functionally redundant in hindbrain development, their amplification in cerebellar granule neural precursor cells leads to different medulloblastoma subtypes. In this project we are employing ribosome profiling on mouse medulloblastoma tumors generated from granule neural precursor cells with enforced expression of Myc or Mycn. Ribosome-protected mRNA sequencing allows us to quantitatively assess the specific transcripts regulated at the level of translation, identify translation regulatory sequences within the mammalian transcriptome, and understand genotype-to-phenotype processes. We discovered that Myc- and Mycn-driven tumors exhibit many more changes at the translational rather than at the transcriptional level. In particular, we found that Mycn-driven medulloblastoma upregulates the translation of Myc target genes, while mRNA levels of those genes show no difference between Myc- and Mycn-driven tumors. Furthermore, we find that the most significant translationally upregulated Myc target genes in the Mycn tumors are transcripts that encode ribosome biogenesis factors. We will further study the role of Myc and Mycn on translational regulation of the medulloblastoma transcriptome using our xenograft model of human iPSC-derived neuroepithelial stem cells overexpressing Myc or Mycn. Our goal is to understand the regulatory function of the translational landscape in Myc- and Mycn-driven medulloblastoma and to decipher the oncogenic signaling cascades leading to different medulloblastoma subtypes.
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40

Balashanmugam, Meenashi Vanathi, Thippeswamy Boreddy Shivanandappa, Sivagurunathan Nagarethinam, Basavaraj Vastrad, and Chanabasayya Vastrad. "Analysis of Differentially Expressed Genes in Coronary Artery Disease by Integrated Microarray Analysis." Biomolecules 10, no. 1 (2019): 35. http://dx.doi.org/10.3390/biom10010035.

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Coronary artery disease (CAD) is a major cause of end-stage cardiac disease. Although profound efforts have been made to illuminate the pathogenesis, the molecular mechanisms of CAD remain to be analyzed. To identify the candidate genes in the advancement of CAD, microarray dataset GSE23766 was downloaded from the Gene Expression Omnibus database. The differentially expressed genes (DEGs) were identified, and pathway and gene ontology (GO) enrichment analyses were performed. The protein-protein interaction network was constructed and the module analysis was performed using the Biological General Repository for Interaction Datasets (BioGRID) and Cytoscape. Additionally, target genes-miRNA regulatory network and target genes-TF regulatory network were constructed and analyzed. There were 894 DEGs between male human CAD samples and female human CAD samples, including 456 up regulated genes and 438 down regulated genes. Pathway enrichment analyses revealed that DEGs (up and down regulated) were mostly enriched in the superpathway of steroid hormone biosynthesis, ABC transporters, oxidative ethanol degradation III and Complement and coagulation cascades. Similarly, geneontology enrichment analyses revealed that DEGs (up and down regulated) were mostly enriched in the forebrain neuron differentiation, filopodium membrane, platelet degranulation and blood microparticle. In the PPI network and modules (up and down regulated), MYC, NPM1, TRPC7, UBC, FN1, HEMK1, IFT74 and VHL were hub genes. In the target genes-miRNA regulatory network and target genes—TF regulatory network (up and down regulated), TAOK1, KHSRP, HSD17B11 and PAH were target genes. In conclusion, the pathway and GO ontology enriched by DEGs may reveal the molecular mechanism of CAD. Its hub and target genes, MYC, NPM1, TRPC7, UBC, FN1, HEMK1, IFT74, VHL, TAOK1, KHSRP, HSD17B11 and PAH were expected to be new targets for CAD. Our finding provided clues for exploring molecular mechanism and developing new prognostics, diagnostic and therapeutic strategies for CAD.
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41

Yashar, William M., Brittany M. Smith, Jake VanCampen, et al. "Abstract 3269: Dual targeting of FLT3 and LSD1 disrupts the MYC super-enhancer complex in acute myeloid leukemia." Cancer Research 82, no. 12_Supplement (2022): 3269. http://dx.doi.org/10.1158/1538-7445.am2022-3269.

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Abstract Clinical responses to kinase inhibitor therapy in acute myeloid leukemia (AML) are limited by development of resistance. A major contributor of resistance is epigenetic adaptation to kinase inhibitor therapy. We present evidence that inhibition of the epigenetic regulator lysine-specific demethylase 1 (LSD1) augments the response to inhibitors of FMS-like tyrosine kinase 3 (FLT3) in FLT3-mutant AML. We demonstrate that combined FLT3 and LSD1 inhibition results in synergistic cell death of FLT3-mutant AML cell lines and primary patient samples. High-resolution epigenetic sequencing revealed that the combination therapy synergistically suppresses pro-proliferative MYC-bound promoters and activates pro-differentiative PU.1-bound enhancers. Regulon enrichment analysis in primary AML samples nominated STAT5 (a downstream target of activated FLT3 signaling) as a putative regulator of MYC gene expression. STAT5 is highly bound to the MYC blood super-enhancer and FLT3 inhibition results in a loss of both STAT5 binding and MYC blood super-enhancer chromatin accessibility. In contrast, LSD1 inhibition suppresses MYC target genes by accumulation of repressive H3K9me1 marks. We validated these findings in 72 primary AML samples, including 19 FLT3-ITD positive AML samples. The combination improved responses in the vast majority of patient samples, and high MYC regulon activity was a predictor of response. Gene expression profiling in treated primary AML samples confirmed that dual FLT3 and LSD1 inhibition activates PU.1 target genes and suppresses MYC target genes. Finally, single cell ATAC-seq on primary AML blasts treated ex vivo with combined FLT3 and LSD1 shifted cells from a MYC super-enhancer high to MYC super-enhancer low state. Collectively, these data provide preclinical rationale for the investigation of dual FLT3 and LSD1 inhibition in clinical trial. Citation Format: William M. Yashar, Brittany M. Smith, Jake VanCampen, Garth L. Kong, Jommel Macaraeg, Daniel J. Coleman, Brian J. Druker, Julia E. Maxson, Theodore P. Braun. Dual targeting of FLT3 and LSD1 disrupts the MYC super-enhancer complex in acute myeloid leukemia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3269.
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42

Scafuro, Marika, Lucia Capasso, Vincenzo Carafa, Lucia Altucci, and Angela Nebbioso. "Gene Transactivation and Transrepression in MYC-Driven Cancers." International Journal of Molecular Sciences 22, no. 7 (2021): 3458. http://dx.doi.org/10.3390/ijms22073458.

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MYC is a proto-oncogene regulating a large number of genes involved in a plethora of cellular functions. Its deregulation results in activation of MYC gene expression and/or an increase in MYC protein stability. MYC overexpression is a hallmark of malignant growth, inducing self-renewal of stem cells and blocking senescence and cell differentiation. This review summarizes the latest advances in our understanding of MYC-mediated molecular mechanisms responsible for its oncogenic activity. Several recent findings indicate that MYC is a regulator of cancer genome and epigenome: MYC modulates expression of target genes in a site-specific manner, by recruiting chromatin remodeling co-factors at promoter regions, and at genome-wide level, by regulating the expression of several epigenetic modifiers that alter the entire chromatin structure. We also discuss novel emerging therapeutic strategies based on both direct modulation of MYC and its epigenetic cofactors.
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43

Morrish, F. "c-MYC apoptotic function is mediated by NRF-1 target genes." Genes & Development 17, no. 2 (2003): 240–55. http://dx.doi.org/10.1101/gad.1032503.

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44

Dang, Chi V. "c-Myc Target Genes Involved in Cell Growth, Apoptosis, and Metabolism." Molecular and Cellular Biology 19, no. 1 (1999): 1–11. http://dx.doi.org/10.1128/mcb.19.1.1.

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45

Guo, Qingbin, Mauro Ruffy, R. Krishna Sanka, Renae Malek, Norman Lee, and Edison T. Liu. "Identification of c-myc target genes using a rat cDNA microarray." Nature Genetics 23, S3 (1999): 49. http://dx.doi.org/10.1038/14318.

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46

Liao, Chengcheng, Sha He, Jie Sun, et al. "A Focused High Throughput Functional Screen Identifies Novel Targets for aggressive B-Cell Lymphoma." Blood 144, Supplement 1 (2024): 5758. https://doi.org/10.1182/blood-2024-209515.

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Introduction: Diffuse large B-cell lymphoma is an aggressive cancer that arises from B-cells and accounts for about 30-40% of all non-Hodgkin lymphoma cases. Genetically, it can be classified as single-hit (SHL: has rearrangement in one of the three genes i.e., MYC, BCL2 or BCL6, typically MYC), double-hit (DHL: involves rearrangements in two of these genes, commonly MYC and either BCL2 or BCL6), triple-hit (THL: involving rearrangements in MYC, BCL2, and BCL6 genes) or no hit (NHL: with no rearrangements in any of these genes). Double and triple hit lymphomas are aggressive with the poor prognosis. In this study, we conducted a genome-wide functional screen in single and double hit cell lines and analyzed the data in comparison with DepMap data. Methods: The SHL cell line Raji (MYC rearranged) and the DHL cell line SU-DHL-10 (MYC and BCL-2 rearranged) with stably integrated Cas9 were transduced (in triplicate) with a genome-wide lentiviral expression library (GeCKO v2) containing 123,411 guides representing 19,050 genes. Cells selected in puromycin were cultured and the DNA from these cells sequenced to identify genes with potential to inhibit lymphoma cell growth. Target genes unique and common to SHL (Raji) and DHL (SU-DHL-10) cells were identified and investigated for functional enrichment. Dependency Map (Cancer DepMap, https://depmap.org/portal/) database was also used to identify the functional target genes for Raji and SU-DHL-10 cells. Target genes identified in SHL (Raji) and DHL (SU-DHL-10) cells in our data and DepMap data were compared for overlap and differences. Results: Loss of function screen identified 373, 267 and 702 genes to be associated with loss of cell viability in Raji (SHL), SU-DHL-10 (DHL) and both Raji and SU-DHL-10 cell lines, respectively. Several metabolic and signaling pathways (cGMP-PKG signaling, fatty acid degradation, pyruvate metabolism and glycolysis/gluconeogenesis) were among prominent pathways associated with 702 common hits. Interestingly, the genes identified in SHL and DHL cell lines also associated with similar metabolic pathways. Elevated expression of 390 out of 702 common hits correlated with poor overall survival(OS) in aggressive B-cell lymphoma dataset; RFC5, RFC3 RPL32 and DIS3 were among top hits. Expression of 198 out of 373 Raji (SHL)-only hits correlated with OS; MYC, MED17 and MAD2L1 were among top hits. Expression of 134 out of 267 SU-DHL-10 (DHL) only hits correlated with OS; ZNF131, DDX21 and FAM122A were among top hits. Comparing our data with DepMap data in SU-DHL-10 cells, we found 599 hits common for both datasets whereas 506 and 370 were unique for our screen and DepMap data, respectively. In Raji cells, 782 hits were common in both datasets whereas 293 and 112 were unique for our screen and DepMap data, respectively. This indicates 72% and 87% overlap in our and DepMap data in Raji and SU-DHL-10 cells, respectively. Top hits (including RFC5, RFC3 RPL32, DIS3, MYC, MED17, MAD2L1, ZNF131, DDX21 and FAM122A) are currently being evaluated in detail in our laboratory. Conclusions: Our small functional screen provides further validation of DepMap data and identifies additional promising targets to inhibit growth of lymphoma cells. Selected hits(including RFC5, RFC3 RPL32, DIS3, MYC, MED17, MAD2L1, ZNF131, DDX21 and FAM122A) which also show correlation with survival of aggressive B-cell lymphoma cells are currently being evaluated in loss and gain of function study in our laboratory.
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47

Lin, Kuo-I., Yi Lin, and Kathryn Calame. "Repression of c-myc Is Necessary but Not Sufficient for Terminal Differentiation of B Lymphocytes In Vitro." Molecular and Cellular Biology 20, no. 23 (2000): 8684–95. http://dx.doi.org/10.1128/mcb.20.23.8684-8695.2000.

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ABSTRACT The importance of c-myc as a target of the Blimp-1 repressor has been studied in BCL-1 cells, in which Blimp-1 is sufficient to trigger terminal B-cell differentiation. Our data show that Blimp-1-dependent repression of c-myc is required for BCL-1 differentiation, since constitutive expression of c-Myc blocked differentiation. Furthermore, ectopic expression of cyclin E mimicked the effects of c-Myc on both proliferation and differentiation, indicating that the ability of c-Myc to drive proliferation is responsible for blocking BCL-1 differentiation. However, inhibition of c-Myc by a dominant negative form was not sufficient to drive BCL-1 differentiation. Thus, during Blimp-1-dependent plasma cell differentiation, repression of c-myc is necessary but not sufficient, demonstrating the existence of additional Blimp-1 target genes.
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48

Flores, Ignacio, Gerard Evan, and María A. Blasco. "Genetic Analysis of Myc and Telomerase Interactions In Vivo." Molecular and Cellular Biology 26, no. 16 (2006): 6130–38. http://dx.doi.org/10.1128/mcb.00543-06.

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ABSTRACT Myc is a transcription factor with pleiotropic effects on tumorigenesis which are likely to be mediated by its target genes. A known Myc transcriptional target is the catalytic subunit of telomerase, Tert. However, the contribution of Tert activation to Myc-induced tumorigenesis in vivo remains unknown. In this study, we addressed the role of telomerase in Myc-induced skin papillomatosis by using compound mice with a switchable Myc gene, Inv-MycERTAM mice, in combination with either telomerase deficiency (Terc−/−) or telomerase overexpression (K5-mTert) in the skin. We first demonstrated that Myc activates telomerase in the skin. With Inv-MycERTAM × Terc−/− mice, we further showed that this telomerase activation is partially required to elicit a full hyperplastic Myc-induced response. The presence of critically short telomeres in late-generation Inv-MycERTAM × Terc−/− mice further reduced the skin lesion induced by Myc. On the other hand, telomerase overexpression in the skin of K5-mTert mice augments Myc-induced hyperplasia in the absence of changes in telomere length, suggesting a direct role of telomerase in the Myc protumorigenic response. Taken together, these results highlight telomerase as a mediator of Myc-induced papillomatosis and suggest telomerase as a putative therapeutic target for Myc-dependent lesions.
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49

Thompson, Zanshé, Georgina A. Anderson, Seth Gabriel, Melanie Rodriguez, Vera Binder, and Katie L. Kathrein. "Ing4-Deficiency Enhances Hematopoietic Stem Cell Quiescence and Confers Resistance to Inflammatory Stress." Blood 138, Supplement 1 (2021): 1095. http://dx.doi.org/10.1182/blood-2021-154353.

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Abstract In a screen for epigenetic regulators of hematopoiesis in zebrafish, we identified a requirement of the tumor suppressor protein, Ing4, in hematopoietic stem and progenitor cell (HSPC) specification. Though the Ing4 mechanism of action remains poorly characterized, loss of Ing4 has been shown to promote stem cell-like characteristics in malignant cells and it is a frequent target of inactivation in various types of cancer. Mutations in Ing4 cause deregulation of both NF-kB and c-Myc target gene expression. We have also identified a requirement for Ing4 in murine hematopoiesis. Ing4-/- mice have aberrant hematopoiesis and elevated cytokine expression in bone marrow cells. Using RNA-sequencing, we found that Ing4-deficient HSPCs express high levels of c-Myc target genes and genes associated with oxidative phosphorylation and ribosomal biogenesis. Yet, Ing4 deficiency induces G 0 arrest in HSPCs and they have low levels of reactive oxygen species. This places Ing4-deficient HSPCs in a poised state, where they are quiescent, but express elevated levels of genes associated with differentiation. Under stress hematopoiesis following low-dose irradiation, Ing4-deficient long-term hematopoietic stem cells (LT-HSCs) do not expand, but short-term hematopoietic stem cells (ST-HSCs) function comparably to wild-type. Similarly, under transplantation stress, LT-HSCs fail to contribute to multilineage chimerism, while ST-HSCs contribute at levels equal to wild-type cells. These results are striking, particularly when compared to other models of enhanced NF-kB activity, where HSPCs cannot contribute to multilineage chimerism in transplantation. We sought to target the misregulated pathways in Ing4-deficient HSCs to rescue to effects of Ing4 deficiency. To this end, we chose to target the c-Myc pathway for several reasons: c-Myc target genes are over-represented in our RNA-seq data, c-Myc lies upstream of several of the misregulated pathways observed in Ing4-/- HSCs, and Ing4 has previously been reported to negatively regulate c-Myc activity directly. When treated with the c-Myc inhibitor, 10058-F4, both LT-HSCs and ST-HSCs are pushed into cycling, but this treatment also resulted in fewer cells overall. These results suggest that dampening of the c-Myc pathway can partially rescue Ing4 loss of function. Overall, our findings suggest that Ing4 plays a crucial role in the regulation of hematopoiesis and provides key tools for further identification and characterization of Ing4 pathways and functions. Given the role of Ing4 in both normal hematopoiesis and cancer, this gene likely has a critical role in regulation of stem cell self-renewal and maintenance. Disclosures No relevant conflicts of interest to declare.
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50

Mu, Yunxiang, Monika A. Zelazowska, and Kevin M. McBride. "Phosphorylation promotes activation-induced cytidine deaminase activity at the Myc oncogene." Journal of Experimental Medicine 214, no. 12 (2017): 3543–52. http://dx.doi.org/10.1084/jem.20170468.

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Activation-induced cytidine deaminase (AID) is a mutator enzyme that targets immunoglobulin (Ig) genes to initiate antibody somatic hypermutation (SHM) and class switch recombination (CSR). Off-target AID association also occurs, which causes oncogenic mutations and chromosome rearrangements. However, AID occupancy does not directly correlate with DNA damage, suggesting that factors beyond AID association contribute to mutation targeting. CSR and SHM are regulated by phosphorylation on AID serine38 (pS38), but the role of pS38 in off-target activity has not been evaluated. We determined that lithium, a clinically used therapeutic, induced high AID pS38 levels. Using lithium and an AID-S38 phospho mutant, we compared the role of pS38 in AID activity at the Ig switch region and off-target Myc gene. We found that deficient pS38 abated AID chromatin association and CSR but not mutation at Myc. Enhanced pS38 elevated Myc translocation and mutation frequency but not CSR or Ig switch region mutation. Thus, AID activity can be differentially targeted by phosphorylation to induce oncogenic lesions.
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