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The MYC oncogene is often dysregulated in human cancer, including hepatocellular carcinoma (HCC). MYC is considered undruggable to date. Here, we comprehensively identify genes essential for survival of MYChigh but not MYClow cells by a CRISPR/Cas9 genome-wide screen in a MYC-conditional HCC model. Our screen uncovers novel MYC synthetic lethal (MYC-SL) interactions and identifies most MYC-SL genes described previously. In particular, the screen reveals nucleocytoplasmic transport to be a MYC-SL interaction. We show that the majority of MYC-SL nucleocytoplasmic transport genes are upregulated in MYChigh murine HCC and are associated with poor survival in HCC patients. Inhibiting Exportin-1 (XPO1) in vivo induces marked tumor regression in an autochthonous MYC-transgenic HCC model and inhibits tumor growth in HCC patient-derived xenografts. XPO1 expression is associated with poor prognosis only in HCC patients with high MYC activity. We infer that MYC may generally regulate and require altered expression of nucleocytoplasmic transport genes for tumorigenesis.

The foremost feature of glioblastoma (GBM), the most frequent malignant brain tumours in adults, is a remarkable degree of intra- and inter-tumour heterogeneity reflecting the coexistence within the tumour bulk of different cell populations displaying distinctive genetic and transcriptomic profiles. GBM with primitive neuronal component (PNC), recently identified by DNA methylation-based classification as a peculiar GBM subtype (GBM-PNC), is a poorly recognized and aggressive GBM variant characterised by nodules containing cells with primitive neuronal differentiation along with conventional GBM areas. In addition, the presence of a PNC component has been also reported in IDH-mutant high-grade gliomas (HGGs), and to a lesser extent to other HGGs, suggesting that regardless from being IDH-mutant or IDH-wildtype, peculiar genetic and/or epigenetic events may contribute to the phenotypic skewing with the emergence of the PNC phenotype. However, a clear hypothesis on the mechanisms responsible for this phenotypic skewing is still lacking. We assumed that the biphasic nature of these entities represents a unique model to investigate the relationships between genetic alterations and their phenotypic manifestations. In this study we show that in HGGs with PNC features both components are highly enriched in genetic alterations directly causing cell cycle deregulation (RB inactivation or CDK4 amplification) and p53 pathway inactivation (TP53 mutations or MDM2/4 amplification). However, the PNC component displays further upregulation of transcriptional pathways associated with proliferative activity, including overexpression of MYC target genes. Notably, the PNC phenotype relies on the expression of EBF3, an early neurogenic transcription factor, which is directly controlled by MYC transcription factors in accessible chromatin sites. Overall our findings indicate that the concomitant presence of genetic alterations, impinging on both cell cycle and p53 pathway control, strongly predisposes GBM to develop a concomitant poorly differentiated primitive phenotype depending on MYC-driven EBF3 transcription in a subset of glioma stem-like progenitor cells. [ABSTRACT FROM AUTHOR]

Osteoarthritis (OA), affecting > 500 million people worldwide, profoundly affects the quality of life and ability to work. The mitogen-activated protein kinase (MAPK) signaling pathway plays an essential role in OA. To address the lack of studies focused on synovial cells in OA, we evaluated the expression patterns and roles of the MAPK signaling pathway components in OA synovial tissues using bioinformatics. The JUN, MYC, and VEGFA expression levels were significantly higher in the synovial tissues of patients with OA than in control tissues. These loci were closely related to abnormal proliferation, inflammation, and angiogenesis in the synovial tissues of patients with OA. We speculate that Myc and VEGFA activate the p38-MAPK signaling pathway to further activate Jun, thereby promoting abnormal inflammation, proliferation, and angiogenesis in OA synovial tissue. The high MYC, JUN, and VEGFA expression was positively correlated with the patients’ K-L score, pain time, and synovial score. Furthermore, the high p38-MAPK and P-p38-MAPK expression confirmed that the abnormal expression and activation of the MAPK signaling pathway occurred in the synovial tissue of patients with OA. Our findings may provide a new direction for the clinical diagnosis and treatment of OA and insights into its pathogenesis. [ABSTRACT FROM AUTHOR]

MYC is one of the most deregulated oncogenic transcription factors in human cancers. MYC amplification/or overexpression is most common in Group 3 medulloblastoma and is positively associated with poor prognosis. MYC is known to regulate the transcription of major components of protein synthesis (translation) machinery, leading to promoted rates of protein synthesis and tumorigenesis. MTOR signaling-driven deregulated protein synthesis is widespread in various cancers, including medulloblastoma, which can promote the stabilization of MYC. Indeed, our previous studies demonstrate that the key components of protein synthesis machinery, including mTOR signaling and MYC targets, are overexpressed and activated in MYC-amplified medulloblastoma, confirming MYC-dependent addiction of enhanced protein synthesis in medulloblastoma. Further, targeting this enhanced protein synthesis pathway with combined inhibition of MYC transcription and mTOR translation by small-molecule inhibitors, demonstrates preclinical synergistic anti-tumor potential against MYC-driven medulloblastoma in vitro and in vivo. Thus, inhibiting enhanced protein synthesis by targeting the MYC indirectly and mTOR pathways together may present a highly appropriate strategy for treating MYC-driven medulloblastoma and other MYC-addicted cancers. Evidence strongly proposes that MYC/mTOR-driven tumorigenic signaling can predominantly control the translational machinery to elicit cooperative effects on increased cell proliferation, cell cycle progression, and genome dysregulation as a mechanism of cancer initiation. Several small molecule inhibitors of targeting MYC indirectly and mTOR signaling have been developed and used clinically with immunosuppressants and chemotherapy in multiple cancers. Only a few of them have been investigated as treatments for medulloblastoma and other pediatric tumors. This review explores concurrent targeting of MYC and mTOR signaling against MYC-driven medulloblastoma. Based on existing evidence, targeting of MYC and mTOR pathways together produces functional synergy that could be the basis for effective therapies against medulloblastoma. [ABSTRACT FROM AUTHOR]

Ferroptosis is the well-known mechanism of septic cardiomyopathy (SCM). Bioinformatics analysis was employed to identify ferroptosis-related SCM differentially expressed genes (DEG). DEGs' functional enrichment was explored. Weighted gene co-expression network analysis (WGCNA) was employed to form gene clusters. The identified hub genes, signal transducer and activator of transcription 3 (STAT3) and myelocytomatosis (MYC) were further evaluated by generating receiver operator characteristic (ROC) curves and a nomogram prediction model. Additionally, survival rate, cardiac damage markers, and cardiac function and ferroptosis markers were evaluated in septic mouse model. STAT3 and MYC levels were measured in SCM heart tissue via immunohistochemical (IHC) staining, real-time polymerase chain reaction (qPCR) and western blot analysis. Analysis identified 225 DEGs and revealed 22 intersected genes. Of the 7 hub genes, STAT3 and MYC showed enrichment in septic heart tissue and a strong predicative ability based on AUC values. Cardiac damage, iron metabolism, and lipid peroxidation occurred in the SCM model. By experiments, STAT3 and MYC expression was increased in the SCM model. Impairment was reversed with a ferroptosis inhibitor, Fer-1. As conclusion, STAT3 and MYC are related with ferroptosis and may serve as potential SCM predictor indicators. Key messages: Septic cardiomyopathy (SCM) often leads to high mortality in septic patients, and the diagnostic criteria still remains unclear. Ferroptosis as the pathogenic mechanism of SCM could help predict its progression and clinical outcomes. STAT3 and MYC are related with ferroptosis and may serve as potential SCM predictor biomarkers. [ABSTRACT FROM AUTHOR]

Background: Double‐expressor lymphoma (DEL) has a poorer prognosis than other subtypes of diffuse large B‐cell lymphoma (DLBCL). This study is a multicenter, prospective, single‐arm, phase 2 clinical study initiated by investigators to evaluate the efficacy and safety of combined zanubrutinib with R‐CHOP, which includes rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone for patients with DEL (stage II or more), as well as to explore factors related to efficacy preliminarily. Methods: From November 2020 to July 2022, 48 newly diagnosed patients were enrolled. All patients received twice‐daily oral zanubrutinib (160 mg) for 6 months and standardized R‐CHOP regimen for six to eight cycles. Results: The objective response rate (ORR) was 89.6%, with a complete response rate (CRR) of 83.3%. The median follow‐up was 29.3 months. The median progression‐free survival (PFS) and overall survival (OS) were not reached. The PFS and OS were 81.25% and 93.75% at 2 years, respectively. Grade ≥3 adverse events (AEs) were reported in 23 of 48 (47.9%) patients. Next‐generation sequencing (NGS) results of 33 patients showed that TP53, MYD88, and PIM1 were the most common mutated gene. Multivariate analysis revealed that BCL‐6 gene rearrangement was an adverse prognostic factor for both PFS (hazard ratio [HR], 0.247; 95% confidence article [CI], 0.068–0.9; p =.034) and OS (HR, 0.057; 95% CI, 0.006–0.591; p =.016), whereas the number of extranodal involvements also significantly influenced OS (HR, 15.12; 95% CI, 1.07–213.65; p =.044). Conclusions: Zanubrutinib in combination with R‐CHOP is an effective option for DEL patients, and the toxicity of zanubrutinib is entirely acceptable for patients. [ABSTRACT FROM AUTHOR]

Double-hit lymphoma (DHL) is a high-risk subtype of large B-cell lymphoma, defined by concurrent rearrangements MYC and BCL2. The diagnosis is confirmed through histologic and immunophenotypic examination and fluorescence in situ hybridization (FISH) to demonstrate the rearrangements. DHL morphology ranges from DLBCL to high-grade B-cell lymphoma which can resemble Burkitt lymphoma and is almost always germinal center B-cell like (GCB). Prognosis is influenced by elevated lactate dehydrogenase (LDH), advanced stage, and extranodal involvement, among other factors. Treatment outcomes vary, but intensive chemotherapy regimens such as dose-adjusted EPOCH-R have shown the most promising results, though low-risk cases do occur and may do well with less intensive treatments. Recent therapeutic advances such as CAR-T cells and bispecific antibodies offer promise for patients with relapsed/refractory disease. This review synthesizes data from recent literature to provide a comprehensive analysis of the molecular underpinnings, diagnostic criteria, prognostic factors, and therapeutic strategies for DHL. [ABSTRACT FROM AUTHOR]

Mitotic arrest-deficient 2 like 1 (MAD2L1) is a component of the mitotic spindle assembly checkpoint implicated in cancer cell proliferation and tumorigenesis. The functional role of MAD2L1 in hepatocellular carcinoma (HCC) has not been adequately investigated, especially in vivo. In the current manuscript, we sought to address the function of MAD2L1 in hepatocarcinogenesis. We found that MAD2L1 expression is upregulated in human HCCs, where its expression is associated with higher aggressive tumor grade, elevated proliferative activity, and poor prognosis. In human HCC cell lines, MAD2L1 knockdown led to decreased cell growth. Moreover, RNA-seq results demonstrated that MAD2L1 silencing induces the expression of genes associated with cell cycle, DNA replication, and various cancer-related pathways, supporting the critical role of MAD2L1 during HCC growth and differentiation. In a c-MYC-induced mouse HCC model, we revealed an increased expression of Mad2l1. Furthermore, Mad2l1 CRIPSR-mediated silencing prevented c-MYC-driven mouse liver development. Altogether, our study suggests that MAD2L1 plays a crucial role in hepatocarcinogenesis, and that its suppression could be a promising therapeutic strategy for treating human HCC. MAD2L1 plays a critical role in liver cancer development, silencing MAD2L1 reduced cell growth in vitro and inhibited c-MYC-driven liver cancer development in vivo. MAD2L1 suppression might be a promising therapeutic approach for treating human liver cancer. [ABSTRACT FROM AUTHOR]

The transcriptional cascade and regulatory loop play crucial roles in regulating plant-specialized metabolite biosynthesis. Capsaicinoids are unique to the genus Capsicum and confer a pungent flavor to its fruits. However, the transcriptional regulation of capsaicinoid biosynthesis remains largely unknown. In this study, two AP2/ERF transcription factors (TFs), CaERF102 and CaERF111, were characterized for their role in the capsaicinoid biosynthesis process. Expression analysis of two ERFs and capsaicinoid biosynthetic genes (CBGs) suggested that they were associated with capsaicinoid biosynthesis. Both ERFs encode nuclear-localized proteins and function as transcriptional activators through their C-terminal activation motifs. The two ERF TFs participated in capsaicinoid biosynthesis by directly activating the promoters of key CBGs, and this activation was significantly enhanced when CaMYC2 was co-expressed. Moreover, CaERF102 and CaERF111 were found to interact with CaMYC2. This study helps elucidate the AP2/ERF TF regulatory network that governs capsaicinoid biosynthesis in Capsicum species. [ABSTRACT FROM AUTHOR]

AbstractIn this review, we focus on the pro-oncogene MYC, the modes of deregulation in mouse and human B-cells, its undisputable importance in the evaluation of biological prognostication of patients, but also how it impacts on response to modern therapeutics, and how it should be targeted to improve the overall survival of chronic lymphocytic lymphoma (CLL) patients. After an overview of the current understanding of the molecular dysregulation of c-MYC, we will show how CLL, both in its indolent and transformed phases, has developed among other B-cell lymphomas a tight regulation of its expression through the chronic activation of B-Cell Receptors (among others). This is particularly important if one desires to understand the mechanisms at stake in the over-expression of c-MYC especially in the lymph nodes compartment. So doing, we will show how this oncogene orchestrates pivotal cellular functions such as metabolism, drug resistance, proliferation and histologic transformation (Richter syndrome). [ABSTRACT FROM AUTHOR]

Background: MYC-driven lymphomas are a subset of B-cell lymphomas characterized by genetic alterations that dysregulate the expression of the MYC oncogene. When overexpressed, typically through chromosomal translocations, amplifications, or other mechanisms, MYC can drive uncontrolled cell growth and contribute to cancer development. MYC-driven lymphomas are described as aggressive entities which require intensive treatment approaches and can be associated with poor prognosis. In the absence of direct MYC-targeting therapy, epigenetic drugs called BET inhibitors (BETi) were shown to reduce MYC levels by disrupting BRD4-dependent transcription associated with the expression of MYC, as well as other oncogenes. Here, we used BETi as molecular tools to better understand oncogenic dependencies in a panel of cell line models of MYC-driven B-cell lymphoma selected to represent their genetic heterogeneity. Results: We first showed that, in these models, MYC expression level does not strictly correlate to the presence of gene alterations. Our data also demonstrated that BETi induces similar growth arrest in all lymphoma cell lines independently of MYC mutational status or expression level. In contrast, BETi-induced cell death was only observed in two cell lines presenting the highest level of MYC protein. This suggests that some MYC-driven lymphoma could present a stronger dependency on MYC for their survival which cannot be predicted on the sole basis on their genetics. This hypothesis was confirmed by gene invalidation experiments, which showed that MYC loss recapitulates the effect of BETi treatment on both cell proliferation and survival, confirming MYC oncogene dependency in models sensitive to BETi cytotoxicity. In contrast, the growth arrest observed in cell lines resistant to BETi-induced apoptosis is not mediated through MYC, but rather through alternative pro-proliferative or oncogenic pathways. Gene expression profiling revealed the basal activation of a specific non-canonical WNT/Hippo pathway in cell death-resistant cell lines that could be targeted in combination therapy to restore BETi cytotoxicity. Conclusion: This work brings new insights into the complexity of MYC-dependencies and unravels a novel targetable oncogenic pathway in aggressive B-cell lymphomas. [ABSTRACT FROM AUTHOR]

Simple Summary: The Epstein–Barr virus (EBV) infection does not induce any apparent pathology in most people but it has been associated with an increased risk of developing a number of non-malignant diseases (e.g., infectious mononucleosis and multiple sclerosis) and some cancers. Among these, the association between EBV and Burkitt lymphoma (BL) is striking, involving a tumor where MYC is deregulated by translocation in all cases. BL is more prevalent in children from equatorial Africa (>90% of the cases) whereas the association of EBV with BL is much lower (25–40%) in other regions. This high association suggests that EBV is a driving mechanism, but whether it is sufficient to trigger lymphomagenesis or it is a cooperative factor is under debate. Indeed, the precise molecular mechanisms underlying the virus activity in infected B cells in collaboration with MYC is still unclear. The molecular mechanisms by which EBV operates in tumor B cells will be discussed. The Epstein–Barr virus (EBV) is associated with a wide range of diseases, malignant and non-malignant. EBV was, in fact, the first virus described with cell transformation capacity, discovered by Epstein in 1964 in lymphoma samples from African children. Since then, EBV has been associated with several human tumors including nasopharyngeal carcinoma, gastric carcinoma, T-cell lymphoma, Hodgkin lymphoma, diffuse large B cell lymphoma, and Burkitt lymphoma among others. The molecular hallmark of Burkitt lymphoma (BL) is a chromosomal translocation that involves the MYC gene and immunoglobulin loci, resulting in the deregulated expression of MYC, an oncogenic transcription factor that appears deregulated in about half of human tumors. The role of MYC in lymphoma is well established, as MYC overexpression drives B cell proliferation through multiple mechanisms, foremost, the stimulation of the cell cycle. Indeed, MYC is found overexpressed or deregulated in several non-Hodgkin lymphomas. Most endemic and many sporadic BLs are associated with EBV infection. While some mechanisms by which EBV can contribute to BL have been reported, the mechanism that links MYC translocation and EBV infection in BL is still under debate. Here, we review the main EBV-associated diseases, with a special focus on BL, and we discuss the interaction of EBV and MYC translocation during B cell malignant transformation in BL. [ABSTRACT FROM AUTHOR]

The Myc family is essential for cell proliferation, differentiation, and metabolism, particularly in embryonic development and stem cell functions. However, the specific role of Myc in porcine early embryonic development is not fully understood. This study observed high Myc expression during the four-cell stage of porcine embryos. Inhibition of Myc using 10058-F4 impaired embryonic development, disrupted energy metabolism, and increased DNA methylation. Mechanistically, these effects were dependent on α-KG, a TCA cycle intermediate and cofactor for TET demethylation enzymes. Sequencing analysis of four-cell embryos post- Myc inhibition revealed downregulation of key metabolic enzymes related to α-KG, such as CS, IDH2, leading to reduced α-KG levels. Supplementation with α-Ketoglutarate (α-KG) mitigated the negative effects of Myc inhibition, including lower blastocyst rates, decreased ATP levels, and increased 5 mC levels. In conclusion, Myc regulates the expression of key metabolic enzymes during the four-cell stage, influencing early embryonic metabolism and epigenetic reprogramming. [ABSTRACT FROM AUTHOR]

Objective To explore the role of MYC in lung cancer cell migration and reveal the mechanism affecting migration. Methods siRNA MYC or pRK5-MYC plasmid was transfected into lung cancer cells A549. Cell migration was examined by wound healing assay. The mRNA expression of candidate genes AKRICI and AKR1C3 was detected by fluorescence quantitative PCR. Dual luciferase reporting assay and chromatin immunoprecipitation assay (ChIP) verified the transcriptional regulation of target genes by MYC. A549 cells were transfected with MYC and AKR1C1 siRNA or pRK5-MYC and pRK5-AKRICI at the same time. Wound healing assay and Transwell were used to examine cell migration and cell invasion respectively. Results Knockdown MYC in A549 cells promoted cell migration, and over-expression of MYC inhibited cell migration. The level of protein and mRNA of AKRIC1 was significantly increased (P<0.01) after knockdown MYC. The ChIP assay showed that MYC binded to the response element (RE) of AKR1C1. Compared with control plasmids, MYC induced the expression of luciferase in RE-containing plasmids. Decreased expression of AKR1C1 inhibited the invasion and migration of lung cancer cells(P<0.05). AKR1C1 reduced cell invasion and migration caused by MYC loss (P<0.05). Conclusions MYC might inhibit cancer cell migration by inhibiting AKR1C1 expression. [ABSTRACT FROM AUTHOR]

Deficient (d) DNA mismatch repair (MMR) is a biomarker predictive of better response to PD-1 blockade immunotherapy in solid tumors. dMMR can be caused by mutations in MMR genes or by protein inactivation, which can be detected by sequencing and immunohistochemistry, respectively. To investigate the role of dMMR in diffuse large B-cell lymphoma (DLBCL), MMR gene mutations and expression of MSH6, MSH2, MLH1, and PMS2 proteins were evaluated by targeted next-generation sequencing and immunohistochemistry in a large cohort of DLBCL patients treated with standard chemoimmunotherapy, and correlated with the tumor immune microenvironment characteristics quantified by fluorescent multiplex immunohistochemistry and gene-expression profiling. The results showed that genetic dMMR was infrequent in DLBCL and was significantly associated with increased cancer gene mutations and favorable immune microenvironment, but not prognostic impact. Phenotypic dMMR was also infrequent, and MMR proteins were commonly expressed in DLBCL. However, intratumor heterogeneity existed, and increased DLBCL cells with phenotypic dMMR correlated with significantly increased T cells and PD-1+ T cells, higher average nearest neighbor distance between T cells and PAX5+ cells, upregulated immune gene signatures, LE4 and LE7 ecotypes and their underlying Ecotyper-defined cell states, suggesting the possibility that increased T cells targeted only tumor cell subsets with dMMR. Only in patients with MYC¯ DLBCL, high MSH6/PMS2 expression showed significant adverse prognostic effects. This study shows the immunologic and prognostic effects of genetic/phenotypic dMMR in DLBCL, and raises a question on whether DLBCL-infiltrating PD-1+ T cells target only tumor subclones, relevant for the efficacy of PD-1 blockade immunotherapy in DLBCL. [ABSTRACT FROM AUTHOR]

Glioblastoma (GBM) is a cancer with high malignancy because of its rapid proliferation and high metastatic ability. LPCAT1 is reported to play a tumor-promoting role in multiple cancers, but its precise molecular mechanism in GBM remains to be further explored. We aim to explore the biological role of LPCAT1 in GBM. In this study, the expression of LPCAT1 and its correlation with clinicopathological characteristics of GBM patients were analyzed based on The Cancer Genome Atlas (TCGA) dataset. Kaplan–Meier approach was adopted for plotting survival curves for patients showing different expression levels of LPCAT1. Meanwhile, LPCAT1 expression within 50 GBM tumor tissues and 30 non-tumor clinical samples was analyzed by qRT-PCR and western blot assays, respectively. Later, LPCAT1's effect on GBM tumorigenesis was analyzed in vivo and in vitro by CCK8, EdU proliferation, clone forming, scratch, TUNEL assays, and subcutaneous xenograft experiments. As a result, LPCAT1 expression elevated within GBM tumor tissues and cells. Overexpression of LPCAT1 enhanced GBM cell growth, invasion and migration, while accelerating cell cycle progression. LPCAT1 silencing significantly inhibited cell motility and proliferation in vivo and in vitro, and arrested U251 cells at G0/G1 phase. Moreover, LPCAT1 might play a role in GBM progression by activating the p-AKT-MYC signaling pathway. LPCAT1 activated AKT, which were synchronously up-regulated MYC to accelerate cancer progression. Knockdown of LPCAT1 induced the opposite changes to repress the viability and motility of GBM cells. LPCAT1 contributed to the progression of GBM by participating in the p-AKT-MYC axis. [ABSTRACT FROM AUTHOR]

Long noncoding RNA (lncRNA) FOXD2 adjacent opposite strand RNA 1 (FOXD2‐AS1) show high expression in various cancers with elusive regulatory mechanisms. This study investigated the regulatory mechanism of FOXD2‐AS1 in clear cell renal cell carcinoma (ccRCC) and its influence on ccRCC cell functions, providing novel insights into ccRCC treatment and a theoretical basis for refining prognoses of ccRCC patients. Through differential analysis and survival analysis, differentially expressed lncRNAs (DElncRNAs) that were significantly linked with the prognosis of ccRCC were initially identified, and lncRNA‐transcription factor‐mRNA triplet was predicted via lncMAP database. RNA immunoprecipitation, chromatin immunoprecipitation, and dual‐luciferase reporter assays were applied to verify the targeted relationship between MYC, FOXD2‐AS1, and Egl‐9 family hypoxia‐inducible factor 3 (EGLN3). Cell functions in ccRCC were detected by a set of cell functional assays. Mice experiment was utilized for in vivo validation. We uncovered the elevated FOXD2‐AS1 and EGLN3 expression in ccRCC, as well as the promotion effect of FOXD2‐AS1 on ccRCC cells to proliferate, migrate, and invade via upregulating EGLN3 expression. Our results also suggested that the regulatory influence of FOXD2‐AS1 on EGLN3 was achieved by recruiting MYC to the EGLN3 promoter region. In vitro and in vivo assays both confirmed that the FOXD2‐AS1/MYC/EGLN3 axis could accelerate the progression of ccRCC. FOXD2‐AS1 activated EGLN3 to accelerate ccRCC cell functions via binding to the transcription factor MYC. [ABSTRACT FROM AUTHOR]

ABSTRACT Introduction Methods Results Conclusion Diffuse large B‐cell lymphoma (DLBCL) exhibits striking clinical and biological heterogeneity. Recent studies have identified new subgroups within germinal center B‐cell like (GCB) DLBCL, associated with inferior prognosis, irrespective of MYC and BCL2 translocations. We explored the existence of such a DLBCL high‐risk subgroup, based on multilevel aberrations, especially focusing on MYC and BCL2.Tissue samples from 111 DLBCL patients were sequenced with a 90‐gene lymphoma panel, followed by integrative analyses combining sequencing data, immunohistochemistry, fluorescent in situ hybridization, and clinical data.We identified a high‐risk subgroup in DLBCL defined by: dual immunohistochemical MYC and BCL2 expression (DEL), concurrent MYC and BCL2 translocations (DHL‐BCL2), mutations in MYC, CXCR4, or both, and/or BCL2 amplification. The high‐risk subgroup constituted 41% of the cohort and included DHL‐BCL2, DEL, a GCB subgroup likely representing the recently described GCB subgroups, and a subset of non‐GCB patients. In multivariate analysis, high‐risk features provided independent predictive value from age and IPI. The 5‐year overall survival was 36% in high‐risk patients, compared to 76% in non‐high‐risk patients.We identified a distinct high‐risk DLBCL subgroup, characterized by MYC and BCL2 aberrations, beyond conventional DHL‐BCL2 and DEL, and irrespective of cell‐of‐origin, thereby expanding the poor‐prognosis group. [ABSTRACT FROM AUTHOR]

Background: Bladder cancer (BLCA) is a common malignancy characterized by dysregulated transcription and a lack of effective therapeutic targets. In this study, we aimed to identify and evaluate novel targets with clinical potential essential for tumor growth in BLCA. Methods: CRISPR-Cas9 screening was used to identify transcription factors essential for bladder cancer cell viability. The biological functions of KLF16 in bladder cancer were investigated both in vitro and in vivo. The regulatory mechanism between KLF16 and MYC was elucidated through a series of analyses, including RNA sequencing, quantitative polymerase chain reaction (qPCR), RNA immunoprecipitation, Western blotting, Mass spectrometry, Dual-luciferase reporter assays, Cleavage Under Targets and Tagmentation (CUT&Tag) sequencing, OptoDroplets assays, and RNA stability assay. The clinical relevance of KLF16 and MYC in bladder cancer was evaluated through analyses of public databases and immunohistochemistry. Results: Krüppel-like factor 16 (KLF16) was essential for BLCA cell viability. Elevated expression of KLF16 was observed in bladder cancer tissues, and higher expression levels of KLF16 were correlated with poor progression-free survival (PFS) and cancer-specific survival (CSS) probabilities in BLCA patients. Mechanistically, KLF16 mRNA competed with the mRNA of dual-specificity phosphatase 16 (DUSP16) for binding to the RNA-binding protein, WW domain binding protein 11 (WBP11), resulting in destabilization of the DUSP16 mRNA. This, in turn, led to activation of ERK1/2, which stabilized the MYC protein. Furthermore, KLF16 interacted with MYC to form nuclear condensates, thereby enhancing MYC's transcriptional activity. Additionally, MYC transcriptionally upregulated KLF16, creating a positive feedback loop between KLF16 and MYC that amplified their oncogenic functions. Targeting this loop with bromodomain inhibitors, such as OTX015 and ABBV-744, suppressed the transcription of both KLF16 and MYC, resulting in reduced BLCA cell viability and tumor growth, as well as increased sensitivity to chemotherapy. Conclusions: Our study revealed the crucial role of the KLF16/MYC regulatory axis in modulating tumor growth and chemotherapy sensitivity in BLCA, suggesting that combining bromodomain inhibitors, such as OTX015 or ABBV-744, with DDP or gemcitabine could be a promising therapeutic intervention for BLCA patients. [ABSTRACT FROM AUTHOR]

Cell competition is an evolutionarily conserved quality control process that eliminates suboptimal or potentially dangerous cells. Although differential metabolic states act as direct drivers of competition, how these are measured across tissues is not understood. Here, we demonstrate that vesicular glutamate transporter (VGlut) and autocrine glutamate signaling are required for cell competition and Myc -driven super-competition in the Drosophila epithelia. We find that the loss of glutamate-stimulated VGlut>NMDAR>CaMKII>CrebB signaling triggers loser status and cell death under competitive settings via the autocrine induction of TNF. This in turn drives TNFR>JNK activation, triggering loser cell elimination and PDK/LDH-dependent metabolic reprogramming. Inhibiting caspases or preventing loser cells from transferring lactate to their neighbors nullifies cell competition. Further, in a Drosophila model for premalignancy, Myc -overexpressing clones co-opt this signaling circuit to acquire super-competitor status. Targeting glutamate signaling converts Myc "super-competitor" clones into "losers," highlighting new therapeutic opportunities to restrict the evolution of fitter clones. [Display omitted] • Glutamate signaling surveys epithelial fitness through cell competition • Loss of glutamate signaling results in autocrine TNF-induced loser elimination • Loser cells undergo metabolic reprogramming and transfer lactate to winners • Mychigh cells promote and depend on glutamate signaling to outcompete neighbors Soares et al. show that differential levels of VGlut>NMDAR>CaMKII-mediated glutamate signaling regulate epithelial fitness, in which loser cells undergo TNF-induced elimination and donate their carbon fuel to winners. Targeting this signaling axis converts Myc super-competitors into losers. [ABSTRACT FROM AUTHOR]

Simple Summary: This review explores the role of c-MYC in Chronic Lymphocytic Leukemia (CLL) and its impact on genetic instability and disease progression. As a key oncogene, c-MYC encodes a transcription factor involved in regulating cell cycle, growth, and apoptosis. We previously described CLL cases enriched with unmutated IGHV genes, MYC overexpression and with active rearrangement of the IGH immunoglobulin heavy chain (IGH) locus. The MYC overexpression seems to promote increased DNA damage, including double-strand breaks (DSBs), chromosomal translocations linked to repair errors during DNA repair. Highlighting c-MYC's dual role, this review try to show how MYC overexpression it not only driving cell proliferation but also contributes to genomic instability. This review examines the pivotal role of c-MYC in Chronic Lymphocytic Leukemia (CLL), focusing on how its overexpression leads to increased genetic instability, thereby accelerating disease progression. MYC, a major oncogene, encodes a transcription factor that regulates essential cellular processes, including cell cycle control, proliferation, and apoptosis. In CLL cases enriched with unmutated immunoglobulin heavy chain variable (IGHV) genes, MYC is significantly overexpressed and associated with active rearrangements in the IGH immunoglobulin heavy chain locus. This overexpression results in substantial DNA damage, including double-strand breaks, chromosomal translocations, and an increase in abnormal repair events. Consequently, c-MYC plays a dual role in CLL: it promotes aggressive cell proliferation while concurrently driving genomic instability through its involvement in genetic recombination. This dynamic contributes not only to CLL progression but also to the overall aggressiveness of the disease. Additionally, the review suggests that c-MYC's influence on genetic rearrangements makes it an attractive target for therapeutic strategies aimed at mitigating CLL malignancy. These findings underscore c-MYC's critical importance in advancing CLL progression, highlighting the need for further research to explore its potential as a target in future treatment approaches. [ABSTRACT FROM AUTHOR]

In B-cell malignancies, the overexpression of MYC is associated with poor prognosis, but its mechanism underlying resistance to immunochemotherapy remains less clear. In further investigations of this issue, we show here that the pharmacological inhibition of MYC in various lymphoma and multiple myeloma cell lines, as well as patient-derived primary tumor cells, enhances their susceptibility to NK cell-mediated cytotoxicity induced by conventional antibodies targeting CD20 (rituximab) and CD38 (daratumumab), as well as T cell-mediated cytotoxicity induced by the CD19-targeting bispecific T-cell engager blinatumomab. This was associated with upregulation of the target antigen only for rituximab, suggesting additional escape mechanisms. To investigate these mechanisms, we targeted the MYC gene in OCI-LY18 cells using CRISPR-Cas9 gene-editing technology. CRISPR-Cas9-mediated MYC targeting not only upregulated CD20 but also triggered broader apoptotic pathways, upregulating pro-apoptotic PUMA and downregulating anti-apoptotic proteins BCL-2, XIAP, survivin and MCL-1, thereby rendering tumor cells more prone to apoptosis, a key tumor-lysis mechanism employed by T-cells and NK-cells. Moreover, MYC downregulation boosted T-cell activation and cytokine release in response to blinatumomab, revealing a MYC-mediated T-cell suppression mechanism. In conclusion, MYC overexpressing tumor cells mitigated the efficacy of therapeutic antibodies through several non-overlapping mechanisms. Given the challenges associated with direct MYC inhibition due to toxicity, successful modulation of MYC-mediated immune evasion mechanisms may improve the outcome of immunotherapeutic approaches in B-cell malignancies. [ABSTRACT FROM AUTHOR]

High-grade osteosarcoma (OS) is the most common primary bone tumor mainly affecting children and young adults. First-line treatment consists of neo-adjuvant chemotherapy with doxorubicin, cisplatin, and methotrexate and surgery. The mean long-term survival rate for localized disease at diagnosis is 65–70%, dropping down to 20% when metastases are present at diagnosis. Therefore, curing OS is a clinical challenge, particularly for patients that do not respond to standard treatments. MYC has frequently been reported to be involved in the pathogenesis of OS and its high expression may be associated with drug resistance and patients' worse prognosis. Moreover, MYC is a master regulator of ribosomal proteins (RPs) synthesis and ribosome biogenesis (RiBi), which is often up-regulated in human tumors. In recent years, RPs have been recognized not only for their traditional role in ribosome assembly but also for their extra-ribosomal functions, many of which are linked to the onset and progression of cancer. In this review we focus on the role and possible interplay of MYC and RPs expression in association with drug resistance and worse prognosis in OS and discuss therapeutic options that target de-regulated MYC, RiBi, or RPs, which are already clinically available or under evaluation in clinical trials. [ABSTRACT FROM AUTHOR]

The overexpression of MYC genes is frequently found in many human cancers, including adult and pediatric malignant brain tumors. Targeting MYC genes continues to be challenging due to their undruggable nature. Using our prediction algorithm, the nine-amino-acid activation domain (9aaTAD) has been identified in all four Yamanaka factors, including c-Myc. The predicted activation function was experimentally demonstrated for all these short peptides in transactivation assay. We generated a set of c-Myc constructs (1–108, 69–108 and 98–108) in the N-terminal regions and tested their ability to initiate transcription in one hybrid assay. The presence and absence of 9aaTAD (region 100–108) in the constructs strongly correlated with their activation functions (5-, 3- and 67-times respectively). Surprisingly, we observed co-activation function of the myc region 69–103, called here acetyl-TAD, previously described by Faiola et al. (Mol Cell Biol 25:10220–10234, 2005) and characterized in this study as a new domain collaborating with the 9aaTAD. We discovered strong interactions on a nanomolar scale between the Myc-9aaTAD activation domains and the KIX domain of CBP coactivator. We showed conservation of the 9aaTADs in the MYC family. In summary for the c-Myc oncogene, the acetyl-TAD and the 9aaTAD domains jointly mediated activation function. The c-Myc protein is largely intrinsically disordered and therefore difficult to target with small-molecule inhibitors. For the c-Myc driven tumors, the strong c-Myc interaction with the KIX domain represents a promising druggable target. [ABSTRACT FROM AUTHOR]

Background: Patients with metastatic hepatoblastoma are treated with severely toxic first-line chemotherapies in combination with surgery. Yet, inadequate response of lung metastases to neo-adjuvant chemotherapy still compromises patient outcomes making new treatment strategies, tailored to more efficient lung clearance, mandatory. Methods: We harnessed a comprehensive patient-derived xenograft platform and a variety of in vitro and in vivo assays to establish the preclinical and biological rationale for a new drug for patients with metastatic hepatoblastoma. Results: The testing of a library of established drugs on patient-derived xenografts identified histone deacetylase inhibitors, most notably panobinostat, to be highly efficacious on hepatoblastoma cells, as compared to non-cancerous cells. Molecularly, the anti-tumor effect of panobinostat is mediated by posttranslational obstruction of the MYC oncoprotein as a result of dual specificity phosphatase 1 upregulation, thereby leading to growth inhibition and programmed cell death. Of clinical importance, upregulation of the MYC target gene nucleophosmin 1 is indicative of response to panobinostat and associated with metastatic disease in patients with hepatoblastoma. The combination of panobinostat with the current SIOPEL 4 induction protocol, consisting of cisplatin and doxorubicin, revealed high synergies already at low nanomolar levels. The simulation of a clinical trial, with this combination therapy, in patient-derived xenograft models, and ultimately heterotypic lung metastasis mimics clearly underscored the potency of this approach. Conclusion: Integrated studies define MYC inhibition by panobinostat as a novel treatment element to be introduced into the therapeutic strategy for patients with metastatic hepatoblastoma. [ABSTRACT FROM AUTHOR]

Lymphocyte activation gene 3 (Lag3) is an inhibitory co-receptor expressed on activated T cells and has been proposed to regulate regulatory T (Treg) cell function. However, its precise modality and mechanisms remain elusive. We generated Treg cell-specific Lag3-mutant mouse models and found that Lag3 was essential for Treg cell control of autoimmunity. RNA sequencing analysis revealed that Lag3 mutation altered genes associated with metabolic processes, especially Myc target genes. Myc expression in Lag3-mutant Treg cells was increased to the level seen in conventional T helper (Th)1-type effector cells and directly correlated with their metabolic profiles and in vivo suppressive functions. The phosphatidylinositol 3-kinase (PI3K)-Akt-Rictor pathway was activated in Lag3-mutant Treg cells, and inhibiting PI3K, Rictor, or lactate dehydrogenase A (Ldha), a key Myc target enzyme converting pyruvate to lactate, was sufficient to restore normal metabolism and suppressive function in Lag3-mutant Treg cells. These findings indicate that Lag3 supports Treg cell suppression partly by tuning Myc-dependent metabolic programming. [Display omitted] • Lag3 expression on Treg cells is required for adequate control of inflammation • Lag3-derived intracellular signals play a key role in Treg cell function • Lag3 regulates Myc expression and the metabolism of Treg cells • Lag3 controls Treg cell metabolism via the PI3K-Akt-Rictor pathway Lag3 is a co-inhibitory receptor expressed on T cells, including Foxp3+ regulatory T cells. However, the mechanism underlying Lag3 functions in Treg cells remains largely unclear. Kim et al. generated Treg-specific Lag3 mutant mice and reported that Lag3 supports Treg cell function by inhibiting Myc expression and altering metabolic profiles through the PI3K-Akt-Rictor pathway. [ABSTRACT FROM AUTHOR]

Despite advancements in treating cutaneous melanoma, patients with acral and mucosal (A/M) melanomas still have limited therapeutic options and poor prognoses. We analyzed 156 melanomas (101 cutaneous, 28 acral, and 27 mucosal) using the Foundation One cancer‐gene specific clinical testing platform and identified new, potentially targetable genomic alterations (GAs) in specific anatomic sites of A/M melanomas. Using novel pre‐clinical models of A/M melanoma, we demonstrate that several GAs and corresponding oncogenic pathways associated with cutaneous melanomas are similarly targetable in A/M melanomas. Other alterations, including MYC and CRKL amplifications, were unique to A/M melanomas and susceptible to indirect targeting using the BRD4 inhibitor JQ1 or Src/ABL inhibitor dasatinib, respectively. We further identified new, actionable A/M‐specific alterations, including an inactivating NF2 fusion in a mucosal melanoma responsive to dasatinib in vivo. Our study highlights new molecular differences between cutaneous and A/M melanomas, and across different anatomic sites within A/M, which may change clinical testing and treatment paradigms for these rare melanomas. [ABSTRACT FROM AUTHOR]

Background Objectives Methods Results Conclusion Small cell lung cancer (SCLC) is a highly aggressive type of lung cancer for which platinum‐based chemotherapy is the standard of care. Despite an initial response to this therapy, patients eventually develop resistance to the chemotherapy.To investigate the potential of capivasertib, an approved drug for advanced breast cancer, to enhance the efficacy of cisplatin in preclinical SCLC models and explore the underlying mechanisms.SCLC cell lines were treated with capivasertib and cisplatin, alone or in combination, to assess cell viability, proliferation, colony formation, and apoptosis. Next, capivasertib's effects, alone and combined with cisplatin, were evaluated in an SCLC mouse model. Mechanistic studies focused on Akt and MYC signaling, with constitutively active Akt overexpression used to assess its role.Capivasertib is active against a panel of SCLC cell lines regardless of cellular origin and genetic profiling with IC50 at a clinically achievable range. Particularly, capivasertib inhibits proliferation and anchorage‐independent colony formation and induces apoptosis in SCLC cells. It significantly augments cisplatin's inhibitory effects in all tested cell lines. Importantly, capivasertib at a non‐toxic dose is effective in delaying SCLC growth in mice and its combination with cisplatin achieves nearly complete tumor growth inhibition. Mechanistic studies confirm that capivasertib inhibits Akt and MYC signaling, and furthermore, that overexpression of constitutively active Akt reversed anti‐SCLC activity of capivasertib.Our work is the first to reveal that Akt inhibition can augment chemotherapy in SCLC, and capivasertib is a useful addition to the treatment armamentarium for SCLC. [ABSTRACT FROM AUTHOR]

Background: Kawasaki disease (KD) is an acute systemic vasculitis that can lead to acquired heart disease in children mostly from in developed countries. The previous research showed that B cells in KD patients underwent a profound change in both the cell numbers and types after intravenous immunoglobulin (IVIG) therapy. Methods: We performed the single-cell RNA-sequencing for the peripheral blood mononuclear cells (PBMCs) from three febrile patients and three KD patients to investigate the possible mechanism underlying B cell developmental dysfunction in KD. The pseudo-time analysis was employed to study the developmental trajectories of the PBMCs in febrile control and KD patients. Results: Overall single-cell expression profiles show that the biological processes of immunity, B cell activation pathway and their related biological entities are repressed in KD patients before IVIG treatment compared to febrile patient and KD patients after IVIG treatment. The differentially expressed gene analyses further demonstrate that B cell signaling pathway is downregulated in B cells and plasma blast cells of KD patients before treatment while cell cycle genes and MYC gene are upregulated in dendritic cells (DCs) and hematopoietic stem and progenitor cells (HSPCs) of KD patients before treatment. The biological process of immune response is upregulated in the HSPCs of KD patients before treatment in our dataset while the biological process of inflammatory response is upregulated in the HSPCs of KD patients before treatment in GSE168732 dataset. Single-cell trajectory analyses demonstrate that KD patients before treatment have a shortened developmental path in which B cells and T cells are failed to differentiate into separate lineages. HSPD1 and HSPE1 genes show an elevated expression level in the early cell development stage of KD patients before treatment accompanied with the repression of MYC, SPI1, MT2A and UBE2C genes. Our analyses of all B cells from KD patients before treatment show most of B cells are arrested in a transitional state with an ill developmental path compared with febrile patients and KD patients after treatment. Conclusion: Our results indicate that the immune premature HSPCs accompanied with the abnormal expression dynamics of cell cycle and SPI1 genes are the mechanism underlying B cell developmental dysfunction in KD patients. [ABSTRACT FROM AUTHOR]

Erythropoiesis is a multistep process of erythroid cell production that is controlled by multiple regulatory factors. Ribosome rescue factor PELO plays a crucial role in cell meiotic division and mice embryonic development. However, the function of PELO in erythroid differentiation remains unclear. Here, we showed that knockdown of PELO increased hemin‐induced erythroid differentiation of K562 and HEL cells, exhibiting a higher number of benzidine‐positive cells and increased mRNA levels of erythroid genes. PELO knockdown inhibited the proliferation and cell cycle progression and promoted apoptosis of K562 cells. Mechanistically, PELO could regulate the expression of KLF10 through interaction with MYC. Moreover, KLF10 knockdown also enhanced erythroid differentiation of K562 and HEL cells induced by hemin. Collectively, our results demonstrated that PELO regulates erythroid differentiation and increases KLF10 expression levels by interacting with MYC. [ABSTRACT FROM AUTHOR]

Telomerase reverse transcriptase promoter mutation (pTERT MT) promotes human carcinogenesis via aberrant expression of telomerase reverse transcriptase (TERT). However, the tumorigenic impact of TERT expression independent of pTERT MT remains unclear despite numerous mechanisms of TERT being suggested. To tackle this issue, we employed comprehensive bioinformatics to assess biological variations noticed among different TERT expression mechanisms. Papillary thyroid cancer (PTC) with pTERT MT (pTERT MT PTC) presented aggressive clinical behavior and exhibited biological profiles associated with cellular immortality and genomic instability. PTC with TERT expression but without pTERT MT (TERT (+) PTC), also exhibited poor clinicopathological characteristics and was enriched with immune responses. In accordance, c-MYC/E2F and nuclear factor kappa B (NFκB) were dominant transcription factors in pTERT MT PTC and TERT (+) PTC, respectively. Notably, we revealed TERT hypermethylated oncological region (THOR) as a potential TERT expressing mechanism in TERT (+) PTC patients. Furthermore, three unique subtypes of papillary thyroid cancer were deciphered using a combination of machine learning-based scoring systems. Our proposed scoring system was clinically significant, especially in microcarcinoma, predicting survival outcomes and inferring therapeutic responses to radioactive iodine therapy. Finally, our analysis was expanded to endocrine-related cancers, unveiling various regulatory mechanisms of TERT with poor clinical outcomes and biological behaviors. [ABSTRACT FROM AUTHOR]

Introduction: Multiple myeloma (MM) is an incurable hematological malignancy with high chromosome instability and heavy dependence on the immunosuppressive bone marrow microenvironment. P53 mutations are adverse prognostic factors in MM; however, clinically, some patients without P53 mutations also exhibit aggressive disease progression. DNp73, an inhibitor of TP53 tumor suppressor family members, drives drug resistance and cancer progression in several solid malignancies. Nevertheless, the biological functions of DNp73 and the molecular mechanisms in myelomagenesis remain unclear. Methods: The effects of DNp73 on proliferation and drug sensitivity were assessed using flow cytometry and xenograft models. To investigate the mechanisms of drug resistance, RNA-seq and ChIP-seq analyses were performed in MM cell lines, with validation by Western blot and RT-qPCR. Immunofluorescence and transwell assays were used to assess DNA damage and cell invasion in MM cells. Additionally, in vitro phagocytosis assays were conducted to confirm the role of DNp73 in immune evasion. Results: Our study found that activation of NF-kB-p65 in multiple myeloma cells with different p53 mutation statuses upregulates DNp73 expression at the transcriptional level. Forced expression of DNp73 promoted aggressive proliferation and multidrug resistance in MM cells. Bulk RNA-seq analysis was conducted to assess the levels of MYCN, MYC, and CDK7. A ChIP-qPCR assay was used to reveal that DNp73 acts as a transcription factor regulating MYCN gene expression. Bulk RNA-seq analysis demonstrated increased levels of MYCN, MYC, and CDK7 with forced DNp73 expression inMMcells. A ChIP-qPCR assay revealed that DNp73 upregulates MYCN gene expression as a transcription factor. Additionally, DNp73 promoted immune evasion of MM cells by upregulating MYC target genes CD47 and PD-L1. Blockade of the CD47/SIRPa and PD-1/PD-L1 signaling pathways by the SIRPa-Fc fusion protein IMM01 and monoclonal antibody atezolizumab significantly restored the anti-MM activity of macrophages and T cells in the microenvironment, respectively. Discussion: In summary, our study demonstrated for the first time that the p53 family member DNp73 remarkably induces proliferation, drug resistance, and immune escape of myeloma cells by directly targeting MYCN and regulating the MYC pathway. The oncogenic function of DNp73 is independent of p53 status in MMcells. These data contribute to a better understanding of the function of TP53 and its family members in tumorigenesis. Moreover, our study clarified that DNp73 overexpression not only promotes aggressive growth of tumor cells but, more importantly, promotes immune escape of MM cells through upregulation of immune checkpoints. DNp73 could serve as a biomarker for immunotherapy targeting PD-L1 and CD47 blockade in MM patients. [ABSTRACT FROM AUTHOR]

Mechanisms regulating the gene expression program at different hypoxia severity levels in patient tumors are not understood. We aimed to determine microRNA (miRNA) regulation of this program at defined hypoxia levels from moderate to severe in prostate cancer. Biopsies from 95 patients were used, where 83 patients received the hypoxia marker pimonidazole before prostatectomy. Forty hypoxia levels were extracted from pimonidazole‐stained histological sections and correlated with miRNA and gene expression profiles determined by RNA sequencing and Illumina bead arrays. This identified miRNAs associated with moderate (n = 7) and severe (n = 28) hypoxia and predicted their target genes. The scores of miRNAs or target genes showed prognostic significance, as validated in an external cohort of 417 patients. The target genes showed enrichment of gene sets for cell proliferation and MYC activation at all hypoxia levels and PTEN inactivation at severe hypoxia. This was confirmed by RT‐qPCR for MYC and PTEN, by Ki67 immunohistochemistry, and by gene set analysis in an external cohort. To assess whether miRNA regulation occurred within the predicted hypoxic regions, a method to quantify co‐localization of multiple histopathology parameters at defined hypoxia levels was applied. A high Ki67 proliferation index co‐localized significantly with hypoxia at all levels. The co‐localization index was strongly associated with poor prognosis. Absence of PTEN staining co‐localized significantly with severe hypoxia. The scores for miRNAs correlated with the co‐localization index for Ki67 staining and hypoxia, consistent with miRNA regulation within the overlapping regions. This was confirmed by showing miR‐210‐3p expression within severe hypoxia by in situ hybridization. Cell line experiments (22Rv1, PC3) were conducted to determine whether miRNAs and target genes were regulated directly by hypoxia. Most of them were hypoxia‐unresponsive, and probably regulated by other mechanisms such as MYC activation. In conclusion, in aggressive, hypoxic prostate tumors, cancer cells exhibit different proliferative gene expression programs that is regulated by miRNAs and depend on whether the cells reside in moderate or severe hypoxic regions. © 2024 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland. [ABSTRACT FROM AUTHOR]

Abstract MYC is one of the most deregulated oncogenic transcription factors in human cancers. MYC amplification/or overexpression is most common in Group 3 medulloblastoma and is positively associated with poor prognosis. MYC is known to regulate the transcription of major components of protein synthesis (translation) machinery, leading to promoted rates of protein synthesis and tumorigenesis. MTOR signaling-driven deregulated protein synthesis is widespread in various cancers, including medulloblastoma, which can promote the stabilization of MYC. Indeed, our previous studies demonstrate that the key components of protein synthesis machinery, including mTOR signaling and MYC targets, are overexpressed and activated in MYC-amplified medulloblastoma, confirming MYC-dependent addiction of enhanced protein synthesis in medulloblastoma. Further, targeting this enhanced protein synthesis pathway with combined inhibition of MYC transcription and mTOR translation by small-molecule inhibitors, demonstrates preclinical synergistic anti-tumor potential against MYC-driven medulloblastoma in vitro and in vivo. Thus, inhibiting enhanced protein synthesis by targeting the MYC indirectly and mTOR pathways together may present a highly appropriate strategy for treating MYC-driven medulloblastoma and other MYC-addicted cancers. Evidence strongly proposes that MYC/mTOR-driven tumorigenic signaling can predominantly control the translational machinery to elicit cooperative effects on increased cell proliferation, cell cycle progression, and genome dysregulation as a mechanism of cancer initiation. Several small molecule inhibitors of targeting MYC indirectly and mTOR signaling have been developed and used clinically with immunosuppressants and chemotherapy in multiple cancers. Only a few of them have been investigated as treatments for medulloblastoma and other pediatric tumors. This review explores concurrent targeting of MYC and mTOR signaling against MYC-driven medulloblastoma. Based on existing evidence, targeting of MYC and mTOR pathways together produces functional synergy that could be the basis for effective therapies against medulloblastoma.

This study provides evidence to support the concept proposed by Kimura et al. in 2023 that the inhibitors of SP1, MYC, and HIF1A should induce strong anticancer activity by reducing the expression of stem cell-related proteins. In LN229 and U87MG glioblastoma cells, either tetra-methyl-O-nordihydroguaiaretic acid (M4N) or tetra-acetyl-O-nordihydroguaiaretic acid (A4N) suppressed SP1 and only a few stem cell-related proteins and induced only a small amount of cell death; in contrast, the combination treatment of M4N with A4N greatly suppressed the expression of SP1, MYC, and HIF1A, as well as all of the stem cell-related proteins examined, and greatly induced cell death. The bioinformatic analysis showed that the proteins associated with SP1, MYC, and HIF1A were specifically involved in the regulation of transcription and that various microRNAs (miRNAs) that had been shown to induce either anti- or procancer activity were associated with SP1, MYC, and HIF1A, which suggested that the inhibition of SP1, MYC, and HIF1A could modulate the transcription of both coding and noncoding RNAs and affect cancers. These data overall supported our concept.

Identifying the cells from which cancers arise is critical for understanding the molecular underpinnings of tumor evolution. To determine whether stem/progenitor cells can serve as cells of origin, we created a Msi2-CreERT2 knock-in mouse. When crossed to CAG-LSL-MycT58A mice, Msi2-CreERT2 mice developed multiple pancreatic cancer subtypes: ductal, acinar, adenosquamous, and rare anaplastic tumors. Combining single-cell genomics with computational analysis of developmental states and lineage trajectories, we demonstrate that MYC preferentially triggers transformation of the most immature MSI2+ pancreas cells into multi-lineage pre-cancer cells. These pre-cancer cells subsequently diverge to establish pancreatic cancer subtypes by activating distinct transcriptional programs and large-scale genomic changes, and enforced expression of specific signals like Ras can redirect subtype specification. This study shows that multiple pancreatic cancer subtypes can arise from a common pool of MSI2+ cells and provides a powerful model to understand and control the programs that shape divergent fates in pancreatic cancer.

Abstract Objective As colorectal cancer (CRC) remains one of the leading causes of cancer-related deaths, understanding novel therapeutic mechanisms is crucial. This research focuses on the role of extracellular vesicles (EVs) from bone marrow stromal cells (BMSCs) in delivering miR-766-3p to CRC cells, targeting the MYC/CDK2 signaling axis. Methods Differentially expressed genes between BMSCs-EVs and CRC were identified using the Gene Expression Omnibus database. miR-766-3p target genes were predicted via TargetScan and RNAInter, with protein interactions analyzed using the STRING database. The analysis included RT-qPCR and Western blot on samples from 52 CRC patients. Characterization of BMSCs-EVs was followed by their functional assessment on CRC cell lines and the normal colon cell line CCD-18CO, evaluating cellular uptake, proliferation, migration, invasion, and apoptosis. Results miR-766-3p was confirmed in BMSCs-EVs and found underexpressed in CRC. BMSCs-EVs transported miR-766-3p to CRC cells, inhibiting their proliferation, migration, and invasion while promoting apoptosis. miR-766-3p targeted MYC, leading to decreased CDK2 transcription. Overexpression of MYC in HCT-116 cells counteracted these effects. In vivo studies showed that BMSCs-EVs carrying miR-766-3p hindered tumor growth. Conclusion The study demonstrates the efficacy of BMSCs-EVs in delivering miR-766-3p to CRC cells, leading to the suppression of the MYC/CDK2 signaling pathway and hindering cancer progression.

MYC has been implicated in the pathogenesis of a wide range of human tumors and has been described for many years as a transcription factor that regulates genes with pleiotropic functions to promote tumorigenic growth. However, despite extensive efforts to identify specific target genes of MYC that alone could be responsible for promoting tumorigenesis, the field is yet to reach a consensus whether this is the crucial function of MYC. Recent work shifts the view on MYC's function from being a gene‐specific transcription factor to an essential stress resilience factor. In highly proliferating cells, MYC preserves cell integrity by promoting DNA repair at core promoters, protecting stalled replication forks, and/or preventing transcription‐replication conflicts. Furthermore, an increasing body of evidence demonstrates that MYC not only promotes tumorigenesis by driving cell‐autonomous growth, but also enables tumors to evade the host's immune system. In this review, we summarize our current understanding of how MYC impairs antitumor immunity and why this function is evolutionarily hard‐wired to the biology of the MYC protein family. We show why the cell‐autonomous and immune evasive functions of MYC are mutually dependent and discuss ways to target MYC proteins in cancer therapy.

Abstract Precision medicine has drastically changed cancer treatment strategies including KRAS-mutant cancers which have been undruggable for decades. While intrinsic or acquired treatment resistance remains unresolved in many cases, epigenome-targeted therapy may be an option to overcome. We recently discovered the effectiveness of blocking small ubiquitin-like modifier (SUMO) signaling cascade (SUMOylation) in MYC-expressing KRAS-mutant cancer cells using a SUMO-activating enzyme E inhibitor TAK-981 that results in SUMOylation inhibition. Interestingly, TAK-981 promoted the degradation of MYC via the ubiquitin–proteasome system. Moreover, combination therapy with TAK-981 and MEK inhibitor trametinib remarkably regressed xenografted KRAS-mutant tumors by accumulating DNA damage and inducing apoptosis. Whereas our recent study revealed immune-independent antitumor efficacy, we evaluated the immune responses of cancer cells and immune cells in this study. We found that TAK-981-induced MYC downregulation promoted the activation of STING followed by Stat1 and MHC class I in KRAS-mutant cancer cells. Activation of dendritic cells or T cells treated with TAK-981 was also verified by upregulated activation markers in dendritic cells or skew-toward effector-like phenotypes in T cells. Furthermore, the enhanced immune-dependent antitumor efficacy of the combination therapy with TAK-981 and trametinib was confirmed by infiltration of immune cells into tumor tissues and immunodepleting-test using immunodepleting antibodies in syngeneic immunocompetent mouse models. Together with our recent study and here, the findings support that combination inhibition of SUMOylation and MEK comprehensively conquers MYC-expressing KRAS-mutant cancers by both immune-dependent and immune-independent antitumor responses.

Abstract Background Long non-coding RNAs (LncRNAs) have been implicated as critical regulators of cancer tumorigenesis and progression. However, their functions and molecular mechanisms in colorectal cancer (CRC) still remain to be further elucidated. Methods LINC00460 was identified by differential analysis between human CRC and normal tissues and verified by in situ hybridization (ISH) and qRT-PCR. We investigated the biological functions of LINC00460 in CRC by in vitro and in vivo experiments. We predicted the mechanism and downstream functional molecules of LINC00460 by bioinformatics analysis, and confirmed them by dual luciferase reporter gene assay, RNA immunoprecipitation (RIP), RNA pull-down, etc. Results LINC00460 was found to be significantly overexpressed in CRC and associated with poor prognosis. Overexpression of LINC00460 promoted CRC cell immune escape and remodeled a suppressive tumor immune microenvironment, thereby promoting CRC proliferation and metastasis. Mechanistic studies showed that LINC00460 served as a molecular sponge for miR-186-3p, and then promoted the expressions of MYC, CD47 and PD-L1 to facilitate CRC cell immune escape. We also demonstrated that MYC upregulated LINC00460 expression at the transcriptional level and formed a positive feedback loop. Conclusions The LINC00460/miR-186-3p/MYC feedback loop promotes CRC cell immune escape and subsequently facilitates CRC proliferation and metastasis. Our findings provide novel insight into LINC00460 as a CRC immune regulator, and provide a potential therapeutic target for CRC patients.

Hypermutation and malignant transformation are potential complications arising from temozolomide treatment of IDH‐mutant gliomas. However, the natural history of IDH‐mutant low‐grade gliomas without temozolomide treatment is actually under‐studied. We retrieved retrospectively from our hospitals paired tumors from 19 patients with IDH‐mutant, 1p19q non‐codeleted Grade 2 astrocytomas where no interim adjuvant treatment with either temozolomide or radiotherapy was given between primary resections and first recurrences. Tissues from multiple recurrences were available from two patients and radiotherapy but not temozolomide was given before the last specimens were resected. We studied the natural molecular history of these low‐grade IDH‐mutant astrocytomas without pressure of temozolomide with DNA methylation profiling and copy number variation (CNV) analyses, targeted DNA sequencing, TERTp sequencing, FISH for ALT and selected biomarkers. Recurrences were mostly higher grades (15/19 patients) and characterized by new CNVs not present in the primary tumors (17/19 cases). Few novel mutations were identified in recurrences. Tumors from 17/19 (89.5%) patients showed either CDKN2A homozygous deletion, MYC or PDGFRA focal and non‐focal gains at recurrences. There was no case of hypermutation. Phylogenetic trees constructed for tumors for the two patients with multiple recurrences suggested a lack of subclone development in their evolution when under no pressure from temozolomide. In summary, our studies demonstrated, in contrast to the phenomenon of temozolomide‐induced hypermutation, IDH‐mutant, 1p19q non‐codeleted Grade 2 astrocytomas which had not been treated by temozolomide, acquired new CNVs at tumor recurrences. These findings improve our understanding of the molecular life history of IDH‐mutant astrocytomas. [ABSTRACT FROM AUTHOR]