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MYC

MYC is a proto-oncogene that encodes a nuclear phosphoprotein functioning as a basic helix-loop-helix leucine zipper (bHLH-LZ) transcription factor, which heterodimerizes with MAX to bind E-box DNA sequences and regulate gene expression critical for cell cycle progression, metabolism, apoptosis, and cellular transformation.^[1]^[2] Located on chromosome 8q24.21 in humans, MYC is ubiquitously expressed across tissues, with particularly high levels in the gallbladder and esophagus, and belongs to a superfamily including MYCL and MYCN that collectively act as master regulators of cellular growth and differentiation.^[1]^[2] In normal cellular physiology, MYC integrates diverse signals from pathways such as WNT and RAS to drive processes like ribosome biogenesis, protein synthesis, and metabolic reprogramming, ensuring tightly controlled proliferation while preventing uncontrolled growth that could lead to senescence or cell death.^[2] Its activity is precisely regulated through transcriptional activation, epigenetic modifications, and post-translational mechanisms, including phosphorylation at serine 62 for stabilization and ubiquitin-mediated degradation via E3 ligases like FBW7.^[2] Dysregulation of MYC, often via genomic amplification of MYC or related family members (observed in approximately 28% of tumors across 33 cancer types) or chromosomal translocations (as in Burkitt lymphoma and multiple myeloma), transforms it into a potent oncogene that promotes hallmarks of cancer including sustained proliferation, genomic instability, angiogenesis, and immune evasion through upregulation of PD-L1 and CD47.^[1]^[2] MYC overexpression is implicated in a wide array of malignancies, serving as a susceptibility locus for cancers such as renal cell carcinoma, ovarian cancer, and bladder cancer, and is associated with poor prognosis due to its role in tumor progression and resistance to therapy.^[1] Despite its central role in tumorigenesis—evidenced by tumor regression upon MYC inactivation in preclinical models—no direct MYC-targeted therapies are clinically approved as of 2025, though promising strategies include small-molecule inhibitors of the MYC-MAX interaction (e.g., Omomyc derivatives), protein degraders, and synthetic lethal approaches exploiting MYC dependency, such as CDK inhibitors, are under investigation in clinical trials.^[2]

Discovery and Molecular Basics

Historical Discovery

The discovery of the MYC proto-oncogene originated from studies of retroviral oncogenesis in the 1970s. The avian myelocytomatosis virus strain MC29 (MC29), a replication-defective retrovirus first isolated in the 1960s but extensively characterized in the 1970s, was observed to rapidly induce myelocytomas, carcinomas, and leukemias in infected chickens. In 1977, researchers identified an unusual 110-kDa viral-related polypeptide produced in MC29-transformed avian cells, leading to the recognition of the v-myc oncogene as the transforming principle within the viral genome; v-myc was a hybrid gene fusing partial gag sequences with novel myc coding regions responsible for tumorigenesis.^[3] This work built on the emerging understanding of retroviral oncogenes, for which J. Michael Bishop and Harold E. Varmus received the 1989 Nobel Prize in Physiology or Medicine for demonstrating their cellular origins.^[4] In 1982, the cellular homolog of v-myc, termed c-myc, was isolated and characterized from normal chicken DNA using molecular cloning techniques, revealing high sequence homology between the viral and cellular genes and confirming c-myc as a proto-oncogene.^[5] Concurrently, the human c-MYC homolog was identified through Southern blotting and cloning experiments on DNA from Burkitt's lymphoma cells, showing that it mapped to chromosome 8 and shared structural similarities with v-myc, including conserved exons encoding functional domains.^[6] These findings established c-MYC as the cellular counterpart to the viral oncogene, with potential roles in normal cellular growth control. By the early 1980s, c-MYC was directly linked to human cancer through cytogenetic and molecular analyses of Burkitt's lymphoma, a B-cell malignancy endemic in certain regions and associated with Epstein-Barr virus. In 1982, studies demonstrated that the characteristic t(8;14)(q24;q32) chromosomal translocation in these tumors juxtaposed the c-MYC locus on chromosome 8 with the immunoglobulin heavy chain (IGH) locus on chromosome 14, leading to deregulation of c-MYC expression via enhancer activation.^[7] Variant translocations t(2;8) and t(8;22) involving light chain loci were also identified, consistently placing c-MYC under immunoglobulin transcriptional control and highlighting its role as a driver of lymphomagenesis.^[8] These discoveries, achieved through restriction enzyme mapping and hybridization probes, marked c-MYC as the first proto-oncogene implicated in a specific human chromosomal abnormality.^[9]

Gene Structure and Genomic Location

The human MYC gene, also known as c-MYC, is located on the long arm of chromosome 8 at the cytogenetic band 8q24.21, with genomic coordinates spanning from 127,735,434 to 127,742,951 on the GRCh38.p14 reference assembly.^[1] This positions it in a region prone to structural variations, though the gene itself consists of three exons distributed over approximately 7.5 kb of genomic DNA.^[1] The first exon is largely non-coding, while exons 2 and 3 encode the functional protein domains, separated by two introns that facilitate alternative processing.^[10] Transcription of MYC is primarily regulated by two tandem promoters, P1 and P2, located upstream of exon 1 and separated by about 150 base pairs. The upstream P1 promoter lacks a TATA box and initiates a longer transcript that includes the full exon 1 sequence, accounting for roughly 25% of total MYC transcripts in normal cells.^[11] In contrast, the downstream P2 promoter features a canonical TATA box and drives the majority of expression (approximately 75%), producing a shorter transcript with a truncated 5' untranslated region.^[11] These promoters respond to distinct regulatory signals, enabling fine-tuned control of MYC expression during cellular processes. The MYC gene exhibits strong evolutionary conservation, reflecting its fundamental role in cellular regulation. Homologs are present across mammals and birds, with the viral oncogene v-myc originating from the cellular c-myc in the avian myelocytomatosis retrovirus MC29.^[5] This conservation extends to more distant eukaryotes, including myc-like genes in invertebrates such as Drosophila melanogaster (dMyc) and even basal metazoans like Hydra vulgaris, where myc and max homologs date back over 600 million years.^[12] Such broad preservation underscores the ancient origins of the Myc network in eukaryotic genome regulation.^[13] Alternative processing of MYC pre-mRNA and mRNA contributes to isoform diversity, primarily through differential translation initiation rather than extensive splicing variants. The predominant isoform, c-Myc1, initiates from a CUG codon in exon 1; c-Myc2 uses an AUG in exon 2; and the short isoform c-MycS starts from a downstream AUG within exon 2, yielding a truncated protein lacking most of the N-terminal transactivation domain.^[1] This c-MycS form retains proliferative functions but has reduced apoptotic activity compared to full-length isoforms.^[14]

Protein Structure and Expression

Protein Domains and Architecture

The human c-Myc protein, the prototypical member of the MYC family, is a 439-amino-acid polypeptide with a calculated molecular mass of approximately 49 kDa.^[15] Its architecture is modular, featuring an intrinsically disordered N-terminal transactivation domain (TAD) spanning residues 1–143, which mediates interactions with transcriptional co-activators and the core machinery. Flanking the TAD are two conserved central regions known as Myc boxes I (MBI, residues 45–63) and II (MBII, residues 129–141), which are short motifs enriched in acidic and proline residues that facilitate protein-protein interactions essential for MYC's regulatory functions.^[16] These Myc boxes are sites of post-translational modifications, including phosphorylation at serine 62 (Ser62) within MBI, which promotes initial stabilization, and threonine 58 (Thr58), also in MBI, which triggers ubiquitin-mediated degradation via recruitment of E3 ligases like FBXW7.^[17] The C-terminal region (residues ~353–439) comprises the basic helix-loop-helix leucine zipper (bHLH-LZ) domain, a bipartite motif critical for DNA binding and dimerization. The leucine zipper (LZ) subdomain forms a coiled-coil alpha-helix that enables heterodimerization with the partner protein MAX, while the adjacent basic region (b) and helix-loop-helix (HLH) motifs position the dimer on DNA. This bHLH-LZ architecture allows the MYC-MAX heterodimer to specifically recognize and bind the canonical E-box sequence 5'-CACGTG-3' in target gene promoters, facilitating transcriptional activation.^[18] Phosphorylation within the bHLH-LZ, such as at serine 373, can further modulate DNA affinity and stability, though these sites are less central than those in the Myc boxes.^[19] Structural studies using nuclear magnetic resonance (NMR) spectroscopy and X-ray crystallography have elucidated the bHLH-LZ conformation, revealing predominantly alpha-helical secondary structures in both the basic region and LZ upon dimerization and DNA engagement. For instance, crystal structures of the MYC-MAX bHLH-LZ complex bound to E-box DNA show the basic regions inserting into the major groove as extended helices, with the HLH motifs stabilizing the dimer interface through hydrophobic packing.^[20] NMR analyses of the apo form (without DNA) indicate residual helical propensity in the basic region, suggesting intrinsic structural flexibility that enhances binding versatility. These models highlight how the bHLH-LZ domain's helical architecture underpins MYC's role in dimerization-dependent transcription, distinct from its N-terminal regulatory elements.^[21]

Expression Patterns in Tissues

MYC displays dynamic spatiotemporal expression patterns that correlate closely with cellular proliferation states during normal development and in adult tissues. In embryonic stem cells, MYC is highly expressed, where it maintains pluripotency and supports self-renewal by amplifying the transcription of active genes essential for these processes.^[22]^[23] During early embryonic stages, MYC levels are initially low but increase significantly during organogenesis, peaking to drive the expansion of progenitor cell populations and lineage commitment in developing organs such as the skin and intestine.^[22] Postnatally, MYC expression is broadly downregulated in most tissues as cells exit the cell cycle and undergo terminal differentiation, thereby restricting its activity to specific renewing compartments.^[22]^[24] In adult physiology, MYC maintains elevated expression in actively proliferating tissues, including the crypts of the small intestine, where it sustains epithelial renewal, and the basal layer of the epidermis in the skin, aligning with regions of high stem cell activity.^[22]^[25]^[26] Similarly, MYC is prominently expressed in immune cells, such as B and T lymphocytes, where it orchestrates proliferation and differentiation in response to antigenic stimuli within lymphoid tissues.^[22]^[27] In contrast, MYC levels are low or undetectable in quiescent or postmitotic differentiated cells, including mature neurons in the brain and skeletal muscle fibers, reflecting its restricted role outside proliferative contexts.^[22]^[28]^[29] These expression patterns have been characterized through various detection methods, including quantitative polymerase chain reaction (qPCR) for mRNA quantification, Western blotting for protein levels, and immunohistochemistry (IHC) to visualize spatial gradients in embryonic and adult tissues.^[22]^[30] For instance, IHC studies on mouse embryos reveal progressive MYC gradients from proliferative zones to differentiating regions during organogenesis.^[31] This distribution underscores MYC's selective association with proliferative states in normal biology.

Biological Functions

Role in Cell Proliferation and Growth

MYC plays a central role in promoting cell proliferation during normal physiological processes by facilitating the transition from the G1 to S phase of the cell cycle. It achieves this by inducing the expression of D-type cyclins (such as cyclin D1 and D2) and cyclin-dependent kinases CDK4 and CDK6, which form active complexes that phosphorylate the retinoblastoma protein (Rb).^[32] Phosphorylated Rb releases E2F transcription factors, enabling the activation of genes required for DNA synthesis and S-phase entry.^[32] This mechanism ensures efficient progression through the cell cycle in response to growth signals in proliferating tissues like embryonic development and tissue regeneration.^[33] In addition to cell cycle control, MYC drives cellular growth by reprogramming metabolism to support biomass accumulation and energy demands. It upregulates glycolytic enzymes, including lactate dehydrogenase A (LDHA), which converts pyruvate to lactate, thereby enhancing aerobic glycolysis even in oxygen-rich environments to generate intermediates for biosynthesis.^[34] MYC also promotes glutaminolysis by increasing expression of glutaminase (GLS), which hydrolyzes glutamine to glutamate for entry into the tricarboxylic acid cycle, providing precursors for amino acid and nucleotide production.^[34] Furthermore, MYC stimulates nucleotide synthesis pathways by activating genes such as phosphoribosyl pyrophosphate synthetase 2 (PRPS2) and enzymes in the pentose phosphate pathway, ensuring sufficient purine and pyrimidine pools for DNA replication.^[34] MYC further supports growth by enhancing ribosome biogenesis and protein synthesis, essential for increasing cellular mass. It directly regulates transcription by RNA polymerases I and III, which produce ribosomal RNA (rRNA) components and 5S rRNA, respectively, leading to elevated ribosome assembly.^[35] This amplification of translational capacity boosts overall protein production, coordinating with metabolic shifts to sustain proliferative demands.^[35] Quantitative studies in rat fibroblasts demonstrate that restoring MYC expression in myc-null cells reduces the cell doubling time from approximately 45 hours to 24 hours, underscoring its potent impact on proliferation rates.^[36]

Transcriptional Activity and Target Genes

MYC functions as a basic helix-loop-helix leucine zipper (bHLH-LZ) transcription factor that dimerizes with MAX to bind canonical E-box sequences (5'-CACGTG-3') in DNA, thereby regulating a substantial portion of the genome. Genome-wide chromatin immunoprecipitation studies indicate that MYC binds to approximately 10-15% of all promoters and enhancers in mammalian cells, preferentially occupying sites at active genomic regions rather than initiating transcription de novo.^[37] In this capacity, MYC primarily acts as a transcriptional amplifier, enhancing the output of genes that are already poised for expression by boosting RNA polymerase II (Pol II) processivity and elongation rates, particularly in highly transcribed loci.^[38] MYC exerts its activating effects through recruitment of co-activator complexes that modify chromatin and facilitate transcription initiation and elongation. Notably, MYC interacts with the TIP60 histone acetyltransferase complex, which includes subunits such as TRRAP, p400, TIP48, and TIP49, to promote histone H3 and H4 acetylation at target sites, thereby opening chromatin structure for Pol II recruitment and activity.^[39] This co-activation mechanism is evident at promoters where MYC binding correlates with increased Pol II occupancy and reduced Pol II pausing, amplifying gene expression without requiring strict E-box dependency in some contexts.^[40] MYC directly regulates diverse target genes involved in core cellular processes, with effects varying by context. For cell cycle progression, MYC activates genes such as CCND1 (encoding cyclin D1) and CDK4 (cyclin-dependent kinase 4), which drive G1/S transition through retinoblastoma protein phosphorylation.^[41]^[42] In metabolism, MYC upregulates glycolytic enzymes and transporters, including GLUT1 (glucose transporter 1) and HK2 (hexokinase 2), to enhance glucose uptake and flux, supporting biomass production in proliferating cells.^[43] Regarding apoptosis, MYC can suppress pro-apoptotic factors like BIM (BCL2L11), thereby promoting survival under stress conditions, though this repression is often indirect via interference with other regulators.^[44] Genome-wide ChIP-seq analyses have revealed that MYC's transcriptional effects are context-dependent, with both activation and repression observed across thousands of binding sites. In normal cells, MYC predominantly activates genes associated with proliferation and metabolism, but in transformed cells with elevated MYC levels, it also represses specific subsets, such as those involved in differentiation or immune surveillance, through recruitment of repressive complexes like G9a for H3K9 methylation.^[45] These studies highlight MYC's dual role, where binding affinity, local chromatin state, and cellular context determine whether a target gene is amplified or silenced.^[46]

Regulation Mechanisms

Transcriptional and Epigenetic Control

The transcription of the MYC gene is tightly regulated by multiple signaling pathways that converge on its promoter and distal regulatory elements. In the canonical Wnt/β-catenin pathway, stabilized β-catenin translocates to the nucleus and forms complexes with TCF/LEF transcription factors, which bind to Wnt-responsive elements (WREs) upstream and downstream of the MYC promoter to activate transcription.^[47] These include a proximal 5' WRE at -889 bp and a distal -335 WRE, which interact via chromatin looping to enhance promoter accessibility and recruit co-activators.^[48] Similarly, Notch signaling activates MYC through the intracellular domain of NOTCH1 (NICD), which binds the RBPJ transcription factor to directly engage the MYC promoter, driving expression in contexts like T-cell leukemia.^[49] This interaction forms part of a feed-forward loop where MYC reinforces Notch targets. Growth factor stimulation, such as via serum or insulin, engages the MAPK/ERK pathway, where ERK phosphorylates and promotes degradation of the Myc repressor Mad1 through RSK, thereby derepressing MYC transcription and enabling proliferation.^[50] Distal enhancers at the 8q24 locus, spanning approximately 3 Mb around MYC, play a pivotal role in its long-range transcriptional control, often forming super-enhancer complexes that amplify expression in proliferative cells. These enhancers, including the Notch-sensitive +81/+84 region, loop to the promoter via Mediator co-activator recruitment, facilitating high-level transcription.^[51] BRD4, a bromodomain protein, binds these super-enhancers to stabilize the transcriptional machinery, and its inhibition disrupts looping and reduces MYC levels in cancers like Merkel cell carcinoma.^[52] Such super-enhancers are enriched in multiple cell types, integrating signals from pathways like Wnt and Notch to sustain MYC output.^[53] Epigenetic modifications further modulate MYC accessibility, with active histone acetylation marking enhancers for transcription. Histone H3 lysine 27 acetylation (H3K27ac) is prominently enriched at 8q24 super-enhancers and the proximal promoter, correlating with BRD4 occupancy and elevated MYC expression in proliferating cells.^[52] In contrast, during differentiation, such as in granulocytes or primed pluripotent cells, loss of H3K27ac at enhancers represses MYC, contributing to cell cycle exit.^[53] DNA methylation at the MYC promoter also enforces silencing in differentiated states, preventing aberrant reactivation and maintaining lineage commitment.^[54] MYC engages in auto-regulatory feedback to fine-tune its expression, notably by directly transcribing the miR-17-92 microRNA cluster, which encodes miR-19 to suppress PTEN and amplify PI3K/AKT signaling, thereby indirectly sustaining MYC activity.^[55] This loop integrates with upstream signals, ensuring balanced proliferation without excessive apoptosis.

Post-transcriptional and Degradation Pathways

The stability of MYC mRNA is primarily regulated post-transcriptionally through AU-rich elements (AREs) located in its 3' untranslated region (3'UTR), which serve as binding sites for RNA-binding proteins that either promote or inhibit mRNA decay. The protein HuR binds to these AREs and stabilizes MYC mRNA by preventing its degradation, thereby enhancing MYC expression in proliferating cells. In contrast, AUF1 (also known as hnRNP D) binds to the same AREs and promotes MYC mRNA destabilization and rapid turnover, acting as a key negative regulator of MYC levels. These opposing actions of HuR and AUF1 on shared target mRNAs, including MYC, allow for fine-tuned control of transcript half-life in response to cellular signals. MicroRNAs further contribute to post-transcriptional repression of MYC by targeting conserved sites in the 3'UTR, leading to mRNA destabilization or translational inhibition. For instance, members of the let-7 family, such as let-7g, directly bind to the MYC 3'UTR, promoting mRNA degradation and reducing MYC protein levels, which suppresses cell proliferation in contexts like epithelial ovarian cancer. Similarly, miR-34a targets the MYC 3'UTR, inducing its decay and downregulating MYC expression to exert tumor-suppressive effects, as observed in endometrial carcinoma cells where miR-34a overexpression decreases MYC alongside other oncogenes. These miRNA interactions exemplify how non-coding RNAs integrate with ARE-mediated control to modulate MYC mRNA abundance. At the protein level, MYC stability is tightly controlled through ubiquitin-proteasome-mediated degradation, with a short half-life of approximately 20-30 minutes in proliferating cells. Phosphorylation at threonine 58 (Thr58) within the N-terminal Myc box I domain serves as a key signal for ubiquitination by the SCF^{Fbw7} E3 ubiquitin ligase complex, which recognizes the phosphorylated site and targets MYC for proteasomal degradation; mutations at Thr58, such as those in human cancers, impair this process and extend MYC half-life. Conversely, phosphorylation at serine 62 (Ser62) by kinases including Aurora A stabilizes MYC by inhibiting the subsequent Thr58 phosphorylation required for SCF^{Fbw7} recognition, thereby delaying degradation and enhancing MYC oncogenic activity.^[56] This dual phosphorylation code within the conserved degron motif thus balances MYC protein turnover.

Role in Disease

Involvement in Oncogenesis

MYC plays a central role in oncogenesis by driving uncontrolled cell proliferation, metabolic reprogramming, and evasion of apoptosis when deregulated. Overexpression of MYC occurs in more than 70% of human cancers, contributing to tumor initiation and progression across diverse malignancies.^[57] This deregulation is particularly prevalent in aggressive tumors such as neuroblastoma, medulloblastoma, and multiple myeloma, where elevated MYC levels correlate with poor prognosis and advanced disease stages.^[58] For instance, in medulloblastoma, MYC amplification is a hallmark of the high-risk Group 3 subtype, promoting rapid tumor growth and metastasis.^[59] In multiple myeloma, MYC rearrangements and overexpression sustain plasma cell proliferation and survival.^[58] The historical association of MYC with lymphoma arose from its identification as the target of chromosomal translocations in Burkitt's lymphoma.^[9] Deregulation of MYC arises through multiple genetic alterations, including gene amplification, chromosomal translocations, and point mutations that stabilize the protein. Amplification of the MYC locus at chromosome 8q24 is common in solid tumors, such as breast and prostate cancers, where it leads to increased gene dosage and transcriptional hyperactivity.^[60]^[61] In breast cancer, MYC amplification is acquired in metastatic lesions and associates with aggressive phenotypes and reduced survival.^[60] Similarly, in prostate cancer, 8q24 amplification disrupts androgen receptor signaling and drives tumor progression.^[62] Chromosomal translocations, most notably t(8;14)(q24;q32), juxtapose MYC with immunoglobulin heavy chain enhancers in Burkitt's lymphoma, resulting in constitutive expression driven by B-cell-specific promoters.^[9] Point mutations, such as the T58A substitution in the MYC Box I domain, impair phosphorylation-dependent ubiquitination and proteasomal degradation, thereby stabilizing the protein and enhancing its oncogenic potential in lymphomas.^[63] In transformation models, MYC cooperates with RAS to induce full malignant conversion, bypassing senescence and promoting anchorage-independent growth. This synergy was first demonstrated in primary rat embryo fibroblasts, where co-expression of MYC and activated RAS enabled tumorigenic transformation.^[64] MYC also drives genomic instability, facilitating additional mutations that accelerate cancer progression; for example, it upregulates activation-induced cytidine deaminase (AID), leading to DNA double-strand breaks at the MYC locus and IgH, which promote oncogenic translocations in B cells.^[65] In vivo, the Eμ-Myc transgenic mouse model recapitulates human Burkitt's lymphoma, with mice developing pre-B-cell lymphomas within months due to MYC overexpression under IgH enhancer control.^[66] These tumors exhibit dependency on stromal microenvironment support, as lymphoma cells rapidly apoptose in vitro without dendritic cell-derived survival signals, highlighting the role of tumor-host interactions in sustaining oncogenesis.^[67]

Associations with Non-Cancer Diseases

MYC overexpression has been observed in peripheral blood lymphocytes from patients with systemic lupus erythematosus (SLE), correlating with enhanced B-cell proliferation and hyperactivity.^[68] In SLE, B lymphocytes exhibit significantly higher c-Myc RNA levels compared to T cells and normal controls, indicating a pathologically activated state that contributes to autoimmune B-cell responses.^[68] This dysregulation aligns with broader roles of MYC in immune cell activation, where elevated expression promotes metabolic reprogramming and proliferation in autoimmune contexts.^[69] In fibrotic conditions such as idiopathic pulmonary fibrosis (IPF), MYC is upregulated in lung tissues and drives the proliferation and differentiation of pulmonary fibroblasts into myofibroblasts.^[70] Specifically, C-MYC activates miR-9-5p to suppress TBPL1 expression, thereby enhancing fibroblast proliferation, collagen deposition, and fibrotic progression in IPF models.^[70] Silencing C-MYC or using inhibitors like 10,058-F4 reduces miR-9-5p levels, upregulates TBPL1, and attenuates fibrosis, highlighting its pro-fibrotic role.^[70] Hypoxia in IPF further amplifies this by derepressing C-MYC through miR-210-mediated repression of its inhibitor MNT, linking environmental stress to myofibroblast activation.^[71] MYC activation in the cardiovascular system shows context-dependent effects, with transient upregulation promoting adaptive cardiac hypertrophy while chronic activation leads to heart failure. Inducible C-Myc expression in adult cardiomyocytes induces myocyte hypertrophy, increases protein synthesis, and reactivates DNA synthesis, mimicking pressure-overload responses without initial functional impairment.^[72] However, sustained Myc induction triggers cell cycle re-entry, mitochondrial defects (including reduced complex I and III activity), increased apoptosis, and severe hypertrophic cardiomyopathy, culminating in ventricular dysfunction and 100% mortality within weeks in mouse models.^[73] In infectious diseases, the HIV Tat protein promotes MYC-mediated metabolic reprogramming in T cells through activation of NF-κB signaling.^[74] This activation enhances glycolysis, glucose uptake, and overall metabolic reprogramming in T cells, promoting proliferation and immune dysregulation that supports viral persistence in HIV infection.^[74]

Therapeutic and Clinical Aspects

Strategies for Targeting MYC

The development of strategies to target MYC has been challenging due to its intrinsically disordered structure and lack of well-defined binding pockets, often described as "undruggable."^[75] Despite this, multiple pharmacological and genetic approaches have emerged to inhibit MYC activity, focusing on disrupting its dimerization, transcriptional regulation, stability, or expression. These methods aim to suppress MYC-driven oncogenesis while minimizing off-target effects in preclinical models. Direct inhibition of MYC has targeted its basic helix-loop-helix leucine zipper (bHLH-LZ) domain, which is essential for dimerization with MAX and subsequent DNA binding. Small molecules such as KI-MS2-008 bind to the bHLH-LZ region of MAX, stabilizing the MAX homodimer and thereby preventing MYC-MAX heterodimer formation. This compound reduces MYC protein levels and target gene expression in MYC-dependent cancer cell lines, demonstrating preclinical efficacy in suppressing tumor growth in mouse models of T-cell lymphoma. Other small molecules, including 10058-F4 and IIA6B17, similarly disrupt the MYC-MAX interaction by binding to the leucine zipper motif, leading to decreased transcriptional activity in vitro.^[75]^[76]^[77] Indirect pharmacological strategies modulate MYC through upstream regulators or stability pathways. BET bromodomain inhibitors, such as JQ1, disrupt the interaction between BRD4 and acetylated histones at super-enhancers, which are critical for high-level MYC transcription in cancers like multiple myeloma. Treatment with JQ1 preferentially evicts BRD4 from MYC super-enhancers, resulting in rapid downregulation of MYC expression and selective inhibition of oncogene-driven proliferation in tumor cells. Complementing this, Aurora kinase inhibitors like alisertib (MLN8237) promote MYC degradation by disrupting the stabilizing complex between Aurora A and the MYC transactivation domain, leading to proteasomal breakdown of MYC protein in neuroblastoma and other MYC-amplified cancers. These inhibitors induce conformational changes in Aurora A that release MYC, enhancing its ubiquitination and turnover.^[78] Genetic approaches leverage nucleic acid-based tools to reduce MYC expression. Antisense oligonucleotides (ASOs), such as conformationally stabilized MYCASOs, hybridize to MYC mRNA, promoting its degradation via RNase H and thereby potently suppressing MYC protein in cancer cell lines. These ASOs exhibit sequence-specific inhibition, with preclinical studies showing reduced tumor progression in MYC-overexpressing models. Similarly, short hairpin RNA (shRNA) constructs achieve MYC knockdown by RNA interference, inhibiting stem-like cell characteristics and proliferation in glioma and breast cancer xenografts, with ongoing exploration in therapeutic vectors for clinical translation.^[79]^[80]^[81] Addressing MYC's undruggability, proteolysis-targeting chimeras (PROTACs) represent an emerging paradigm by recruiting E3 ubiquitin ligases to enhance MYC ubiquitination and proteasomal degradation. MYC-directed PROTACs, such as those linking MYC-binding motifs to cereblon ligands, induce bimodal degradation in preclinical settings, bypassing traditional binding pocket requirements and offering potential for broader applicability in MYC-driven malignancies.^[82]

Clinical Applications and Challenges

MYC serves as a valuable biomarker in clinical oncology. In a subset of high-risk pediatric neuroblastomas without MYCN amplification, MYC overexpression and rare 8q24 amplification contribute to aggressive disease and poor prognosis, identifiable via fluorescence in situ hybridization (FISH) and immunohistochemistry (IHC).^[83]^[84] In diffuse large B-cell lymphoma (DLBCL), elevated MYC expression assessed via IHC is a robust prognostic indicator, with high levels correlating to significantly reduced overall survival rates, independent of other factors like MYC/BCL2 co-expression.^[85] Ongoing clinical trials explore direct MYC inhibition as a therapeutic avenue in MYC-driven malignancies. For instance, phase I studies of DCR-MYC, a lipid nanoparticle-formulated RNAi therapeutic targeting MYC mRNA, have demonstrated tolerability and preliminary antitumor activity in patients with advanced solid tumors, including reductions in tumor size, with results reported as of 2025.^[86]^[87] Similarly, the dominant-negative MYC inhibitor OMO-103 has advanced through phase I dose-escalation and into phase 2 trials in solid tumors as of 2025, including for advanced osteosarcoma, showing manageable safety profiles and hints of efficacy in MYC-overexpressing subsets.^[88]^[89]^[90] Combination strategies integrating MYC inhibitors with immunotherapy hold promise for enhancing response in MYC-amplified cancers. Preclinical data support pairing MYC blockade with PD-1 inhibitors, where MYC suppression boosts T-cell infiltration and sensitizes tumors to checkpoint blockade, as evidenced by improved tumor regression in models; early-phase trials are now evaluating such synergies in MYC-driven solid tumors.^[91] Despite these advances, translating MYC-targeted therapies to the clinic faces substantial hurdles. MYC's essential role in normal cellular proliferation—regulating up to 15% of the genome—predisposes inhibitors to on-target toxicity, including gastrointestinal and hematopoietic adverse effects observed in early trials.^[92] Additionally, resistance emerges through bypass mechanisms, such as activation of parallel survival pathways like PI3K/AKT, which sustain tumor growth despite MYC inhibition and necessitate combination regimens to circumvent adaptive responses.^[93] These challenges highlight the need for tumor-selective delivery and biomarker-driven patient selection to optimize therapeutic indices.

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Genome Recognition by MYC - PMC - NIH
MYC dimerizes with MAX to bind DNA, with a preference for the E-box consensus CACGTG and several variant motifs. In cells, MYC binds DNA preferentially within ...
[20]
Structural and Biophysical Insights into the Function of the ... - PMC
Apr 22, 2020 · Myc is a transcription factor driving growth and proliferation of cells and involved in the majority of human tumors.
[21]
Crystal Structures and Nuclear Magnetic Resonance Studies of the ...
Crystal Structures and Nuclear Magnetic Resonance Studies of the Apo Form of the c-MYC:MAX bHLHZip Complex Reveal a Helical Basic Region in the Absence of DNA.Missing: bHLH- | Show results with:bHLH-
[22]
Crystal Structures and Nuclear Magnetic Resonance Studies of the ...
Jul 1, 2019 · The N-terminal domain contains the transcription activation domain (TAD) and two highly conserved sequence elements, known as “MYC boxes” (MBI ...Materials and Methods · Results and Discussion · Conclusions · References
[23]
Control of Vertebrate Development by MYC - PMC - PubMed Central
After organogenesis commences, MYCN is down-regulated in most if not all ... Expression of cellular oncogenes during embryonic and fetal development of the mouse.
[24]
myc maintains embryonic stem cell pluripotency and self-renewal
Aug 5, 2010 · The three main myc family members are involved in fundamental normal cellular processes including proliferation, differentiation, and apoptosis ...
[25]
Manipulating Myc for reparative regeneration - PMC - PubMed Central
N-myc expression is significantly downregulated in terminally differentiated adult tissues, whereas c-myc expression persists in some adult tissues such as ...<|separator|>
[26]
c-Myc Is Required for the Formation of Intestinal Crypts but ...
c-myc is a known target of the Wnt pathway in intestinal cells (19, 38, 53) and has been shown to alter the expression of cell adhesion genes such as ...
[27]
Skin epidermis lacking the c-myc gene is resistant to Ras-driven ...
In the mammalian skin epidermis, c-Myc is expressed in the basal layer and the hair bulb, as well as the bulge region correlating with the proliferative and ...
[28]
c-Myc controls the development of CD8αα TCRαβ intestinal ...
Jun 3, 2010 · c-Myc controls the development of CD8αα TCRαβ IELs from thymic precursors by regulating interleukin-15 receptor expression and consequently Bcl-2–dependent ...
[29]
Making Sense of MYC in Skeletal Muscle: Location, Duration, and ...
MYC levels are typically low or undetectable in healthy adult skeletal muscle tissue, but MYC transcript and protein is upregulated in muscle fiber nuclei ...
[30]
Low-level expression of Cmyc in mature neurons - PubMed
Apr 29, 2025 · Cmyc , a proto-oncogene, is expressed at extremely low levels in mature neurons and is traditionally thought to have no function in these cells.
[31]
Tissue expression of MYC - Summary - The Human Protein Atlas
A summary of the overall protein expression pattern across the analyzed normal tissues. ... Muscle tissues. Heart muscle · Skeletal muscle · Smooth muscle ...
[32]
c-myc protein in normal tissue. Effects of fixation on its ... - PMC - NIH
The c-myc protein is thought to be a DNA-associated nuclear protein. However, immunohistochemical studies on normal or tumor tissues have shown conflicting ...
[33]
MYC Oncogene Contributions to Release of Cell Cycle Brakes - MDPI
MYC has been reported to induce the expression of D-type cyclins and CDK4/6 by repressing these miRNAs. Altogether, MYC induces the formation of cyclin D ...Myc Oncogene Contributions... · 3. Myc And P21 Regulation · 4. Myc And P27 Regulation
[34]
Division of labour between Myc and G1 cyclins in cell cycle ... - Nature
Sep 1, 2014 · The potent oncogene, Myc, dramatically affects E2F activity, presumably through modulating G1 cyclins expression as well as cyclin-dependent ...
[35]
Regulation of cancer cell metabolism: oncogenic MYC in the driver's ...
Jul 10, 2020 · Even in a single tumor cell, MYC may simultaneously promote both GS and GLS expression, as these two reactions occur at different subcellular ...
[36]
From the editors - Nature Reviews Molecular Cell Biology
**Summary of MYC's Role in Ribosome Biogenesis, RNA Pol I/III, and Protein Synthesis**
[37]
A Functional Screen for Myc-Responsive Genes Reveals Serine ...
Rat-1 fibroblasts, rat c-myc-null fibroblasts (HO15.19 cells), HO15.19 cells ... The doubling time of the c-myc-null cells decreased from 47.1 ± 1.9 h ...
[38]
Deep Sequencing of MYC DNA-Binding Sites in Burkitt Lymphoma
MYC is a transcription factor encoded by the c-MYC gene (thereafter termed MYC) which regulates an estimated 15% of genes in the human genome [1]. ... The typical ...
[39]
MYC recruits the TIP60 histone acetyltransferase complex to chromatin
Here, we show that MYC associates with TIP60 and recruits it to chromatin in vivo with four other components of the TIP60 complex: TRRAP, p400, TIP48 and TIP49.
[40]
Tip60 complex binds to active Pol II promoters and a subset of ...
Nov 6, 2015 · Our study suggests that the Tip60 complex functions as a global transcriptional co-activator at most active Pol II promoters, co-regulates the ESC-specific c- ...
[41]
c-Myc target gene specificity is determined by a post-DNAbinding ...
First, it is possible that DNA-binding specificity between family members occurs at certain E box elements in vivo. Second, a post-DNA-binding mechanism may ...Missing: source | Show results with:source
[42]
Identification of CDK4 as a target of c-MYC - PMC - NIH
Likewise, c-MYC and CDK4 genes can both immortalize primary cells (22, 23). Induction of CDK4 mRNA was detectable as early as 6 h after infection with Ad-Myc ...Missing: source | Show results with:source
[43]
Genome-wide mapping of Myc binding and gene regulation ... - Nature
Aug 22, 2011 · The c-myc gene product, Myc, is a transcription factor that can either activate or repress gene expression. Activation occurs through ...
[44]
Regulation of MYC gene expression by aberrant Wnt/β-catenin ... - NIH
Aberrant Wnt/β-catenin signaling drives MYC expression in colorectal cancer via β-catenin/TCF complexes binding to WREs, often through long-range chromatin ...
[45]
A β-catenin/TCF-coordinated chromatin loop at MYC integrates 5
Dec 29, 2009 · We propose that a distinct chromatin architecture coordinated by β-catenin/TCF-bound WREs accompanies transcriptional activation of MYC gene expression.
[46]
NOTCH1 directly regulates c-MYC and activates a feed-forward-loop ...
Using an integrative systems biology approach we show that NOTCH1 controls a feed-forward-loop transcriptional network that promotes cell growth.
[47]
Activation of PI3K/Akt and MAPK pathways regulates Myc ... - PNAS
Our findings provide a novel mechanism by which the growth factor signaling pathways cooperate with Myc to promote proliferation and cellular transformation.
[48]
The MYC enhancer-ome: Long-range transcriptional regulation of ...
Of note, we will focus on the enhancer regions of MYC identified in the 8q24 locus, not on the translocations that juxtapose MYC with other enhancer regions ...
[49]
Disruption of BRD4 at H3K27Ac-enriched Enhancer ... - PubMed - NIH
May 5, 2015 · Here we show that an enhancer proximal to the c-Myc promoter is enriched in H3K27Ac and associated with high occupancy of BRD4, and coincides with a putative c ...
[50]
Regulation of Myc transcription by an enhancer cluster dedicated to ...
May 10, 2024 · Here we use genomic rearrangements, transgenesis and targeted mutation to analyse Myc regulation in early mouse embryos and pluripotent stem cells.
[51]
DNA methylation: an epigenetic mark of cellular memory - Nature
Apr 28, 2017 · DNA methylation is a stable epigenetic mark that can be inherited through multiple cell divisions. During development and cell differentiation, DNA methylation ...
[52]
Tumorigenicity of the miR-17-92 cluster distilled
The miR-17-92 cluster is a direct transcriptional target of c-Myc. miR-17/20a targets E2F1, a regulator of the cell cycle and apoptosis. miR-92 targets BIM, a ...
[53]
Phosphorylation Regulates c-Myc's Oncogenic Activity in the ...
Feb 1, 2011 · Phosphorylation of c-Myc at conserved residues serine 62 (S62) and threonine 58 (T58) can regulate c-Myc protein stability in response to ...
[54]
Alternative approaches to target Myc for cancer treatment - Nature
Mar 10, 2021 · The deregulation of Myc occurs in >70% of human cancers, and is related to poor prognosis; hence, hyperactivated Myc oncoprotein has been ...
[55]
MYC Deregulation in Primary Human Cancers - MDPI
May 25, 2017 · In cancer, the activity of the MYC transcriptional network is frequently deregulated, contributing to the initiation and maintenance of disease.
[56]
PRMT5 in MYC-Amplified Medulloblastoma - Encyclopedia.pub
Jan 3, 2024 · MYC amplification or overexpression is most common in Group 3 medulloblastomas and is positively associated with poor clinical outcomes.<|separator|>
[57]
MYC gene amplification is often acquired in lethal distant breast ...
Nov 4, 2011 · In breast cancer, amplification of MYC is consistently observed in aggressive forms of disease and correlates with poor prognosis and ...
[58]
Nuclear MYC protein overexpression is an early alteration in human ...
Jun 20, 2008 · A region on chromosome 8q24 encompassing the MYC locus is amplified in prostate cancer, but this occurs mostly in advanced disease suggesting ...
[59]
MYC drives aggressive prostate cancer by disrupting transcriptional ...
May 13, 2022 · Our findings suggest that MYC overexpression antagonizes the canonical AR transcriptional program and contributes to prostate tumor initiation and progression.<|separator|>
[60]
c-Myc hot spot mutations in lymphomas result in inefficient ...
Our results show that proteasome-mediated turnover of c-Myc is substantially impaired in Burkitt's lymphoma cells with mutated Thr58 or other mutations that ...Abstract · Materials and methods · Results · Discussion
[61]
Tumorigenic conversion of primary embryo fibroblasts requires at ...
Aug 18, 1983 · Transfection of embryo fibroblasts by a human ras oncogene does not convert them into tumour cells unless the fibroblasts are established ...
[62]
The E mu-myc transgenic mouse. A model for high ... - PubMed - NIH
Feb 1, 1988 · Mice transgenic for a c-myc gene driven by the IgH enhancer (E mu-myc) were shown to almost invariably develop lymphomas, 90% succumbing in ...Missing: stromal | Show results with:stromal
[63]
Dendritic cell-mediated survival signals in Eμ-Myc B-cell lymphoma ...
Sep 30, 2014 · In vitro, Eμ-Myc lymphoma B cells undergo rapid apoptosis in the absence of stromal support, a property shared with human acute lymphoblastic ...
[64]
Increased proto-oncogene expression in peripheral blood ... - PubMed
T and B lymphocytes from these patients were found to have significantly increased expression of c-myc, c-myb, and c-raf RNA when compared with those of normal ...
[65]
MYC in Regulating Immunity: Metabolism and Beyond - PubMed - NIH
Feb 25, 2017 · Emerging evidence suggests that MYC family members play essential roles in regulating the development, differentiation and activation of immune cells.
[66]
C-MYC induces idiopathic pulmonary fibrosis via modulation of miR ...
Feb 3, 2022 · We sought to pinpoint the potential role of C-MYC in pulmonary fibroblast proliferation in idiopathic pulmonary fibrosis (IPF) and its mechanism ...
[67]
miR-210 promotes IPF fibroblast proliferation in response to hypoxia
Aug 15, 2014 · Idiopathic pulmonary fibrosis (IPF) is characterized by the ... c-myc inhibitor, MNT. In situ analysis of IPF lung tissue demonstrates ...
[68]
Inducible activation of c-Myc in adult myocardium in vivo ... - PubMed
Activation of Myc in adult myocardium was sufficient to reproduce the characteristic changes in myocyte size, protein synthesis, and cardiac-specific gene ...Missing: failure | Show results with:failure
[69]
Cell cycle re-entry and mitochondrial defects in myc ... - PubMed
Our findings indicate that the induction of Myc in cardiomyocytes is sufficient to cause cardiomyopathy and heart failure.
[70]
Metabolic signaling in T cells | Cell Research - Nature
Jul 24, 2020 · Myc mRNA and c-Myc protein levels in activated T cells are also ... This axis specifically is the target of the HIV Tat protein, which ...
[71]
Therapeutic targeting of “undruggable” MYC - PMC - PubMed Central
KI-MS2-008 reduces the expression of MYC target genes and cancer cell growth in MYC-dependent cell lines and suppresses tumor growth in mouse models of T-cell ...Missing: 062 | Show results with:062
[72]
MYC: a multipurpose oncogene with prognostic and therapeutic ...
Aug 9, 2021 · MYC oncogene is a transcription factor with a wide array of functions affecting cellular activities such as cell cycle, apoptosis, DNA damage response, and ...
[73]
Selective Inhibition of Tumor Oncogenes by Disruption of Super ...
Apr 11, 2013 · Treatment of MM tumor cells with the BET-bromodomain inhibitor JQ1 led to preferential loss of BRD4 at super-enhancers and consequent ...
[74]
Selective targeting of MYC mRNA by stabilized antisense ...
MYCASOs are stabilized antisense oligonucleotides designed to target MYC mRNA, using LNA bases, phosphorothioate backbone, and internal DNA bases.Missing: 412 | Show results with:412<|control11|><|separator|>
[75]
RNAi-Mediated Silencing of Myc Transcription Inhibits Stem-like Cell ...
This important study offers a preclinical proof of concept to target Myc function in cancer stem-like cells as a general strategy to attack most if not.Abstract · Introduction · Results · Discussion<|control11|><|separator|>
[76]
MYC-Targeting PROTACs Lead to Bimodal Degradation and N ...
Mar 27, 2025 · Our studies suggest that PROTACs can promote unconventional events when bringing the ubiquitin–proteasomal–system machinery together with ...Missing: enhancement | Show results with:enhancement
[77]
The role of cytogenetics and molecular diagnostics in the diagnosis ...
High-level amplification of MYC (8q24) is a consistent hallmark of ... The current risk stratification scheme used by the Children's Oncology Group (COG) ...
[78]
MYC/BCL2 protein coexpression contributes to the inferior survival ...
May 16, 2013 · DLBCL patients with MYC/BCL2 coexpression demonstrate inferior prognosis and high-risk gene expression signatures. Diffuse large B-cell lymphoma ...
[79]
Research progress on non-protein-targeted drugs for cancer therapy
Mar 14, 2023 · This paper summarizes the research progress of the non-protein target drugs, mainly RNA-based drugs in cancer treatment in recent years.
[80]
MYC targeting by OMO-103 in solid tumors: a phase 1 trial - PMC
In this first-in-human phase 1 dose-escalation trial of OMO-103, a MYC inhibitor, in patients with solid tumors, treatment was safe and showed preliminary ...Missing: antisense | Show results with:antisense
[81]
Combinatorial immunotherapies overcome MYC-driven immune ...
Jun 27, 2022 · MYC-elevated tumors are less sensitive to anti-PD-L1 in preclinical models. To understand how MYC might alter response to immune checkpoint ...
[82]
MYC and therapy resistance in cancer: risks and opportunities - PMC
An example of bypass resistance is the activation of PI3K signaling by amplification of the MET oncogene in lung cancer resistant to EGFR inhibitor [57].