Entry - *190080 - MYC PROTOONCOGENE, bHLH TRANSCRIPTION FACTOR; MYC

The MYC protooncogene encodes a DNA-binding factor that can activate and repress transcription. Via this mechanism, MYC regulates expression of numerous target genes that control key cellular functions, including cell growth and cell cycle progression. MYC also has a critical role in DNA replication. Deregulated MYC expression resulting from various types of genetic alterations leads to constitutive MYC activity in a variety of cancers and promotes oncogenesis (Dominguez-Sola et al., 2007).

▼ Cloning and Expression

Persson and Leder (1984) showed that the product of the MYC gene has a molecular mass of 65 kD, is located predominantly in the nucleus, and binds to DNA.

▼ Mapping

Leder (1982) described in situ hybridization observations suggesting that the MYC gene is on chromosome 8 near 8q24, the breakpoint in Burkitt lymphoma (113970) translocations.

By the Southern blotting technique applied to somatic cell hybrids, Dalla-Favera et al. (1982) showed that the MYC gene is on chromosome 8. When hybrids between rodent cells and human Burkitt lymphoma (113970) cells were analyzed, Dalla-Favera et al. (1982) could show that the MYC gene is on the part of chromosome 8 (8q24-qter) that is translocated to 2, 14, or 22. Several MYC-related sequences may be pseudogenes. Taub et al. (1982) also mapped the MYC gene to chromosome 8q24.

By fluorescence in situ hybridization in combination with R banding, Takahashi et al. (1991) refined the assignment of MYC to chromosome 8q24.12-q24.13, distal to fragile site fra(8)(q24.11).

▼ Gene Function

Cell proliferation is regulated by the induction of growth promoting genes and the suppression of growth inhibitory genes. Malignant growth can result from the altered balance of expression of these genes in favor of cell proliferation. Induction of the transcription factor MYC promotes cell proliferation and transformation by activating growth-promoting genes, including the ornithine decarboxylase (ODC1; 165640) and CDC25A (116947) genes. Lee et al. (1997) showed that MYC transcriptionally represses the expression of the growth arrest gene (GAS1; 139185). A conserved MYC structure, MYC box 2, is required for repression of GAS1 and for MYC induction of proliferation and transformation, but not for activation of ODC1.

The MYC protein activates transcription as part of a heteromeric complex with MAX (154950). However, cells transformed by MYC are characterized by the loss of expression of numerous genes, suggesting that MYC may also repress gene expression. By searching for proteins that may mediate gene repression by MYC, Peukert et al. (1997) identified ZNF151 (604084), which they called MIZ1 for 'MYC-interacting zinc finger protein-1.' MIZ1 interacts specifically with the helix-loop-helix domain of MYC and NMYC. The predicted MIZ1 protein contains a POZ (poxvirus and zinc finger) domain, which appears to act as a negative regulatory domain for transcription factor function, and 13 zinc finger domains. MIZ1 has a potent growth arrest function and can bind to and transactivate the adenovirus major late and cyclin D1 (CCND1; 168461) promoters. Interaction between MIZ1 and MYC overcomes MIZ1-induced growth arrest, inhibits MIZ1 transactivation, induces MIZ1 nuclear sequestration, and renders MIZ1 insoluble in vivo. These effects depend on the integrity of the POZ domain of MIZ1. Peukert et al. (1997) suggested that MYC inhibits gene transcription by activating the latent inhibitory functions of the MIZ1 POZ domain.

Grandori et al. (1996) identified DDX18 (606355) as a direct in vivo target of Myc and Max and hypothesized that Myc may exert its effects on cell behavior through proteins that affect RNA structure and metabolism.

He et al. (1998) provided a molecular framework for understanding the previously enigmatic overexpression of MYC in colorectal cancers (CRCs; 114500). Inactivating mutations in the adenomatous polyposis coli gene (APC; 611731), found in most colorectal cancers, cause aberrant accumulation of beta-catenin (CTNNB1; 116806), which then binds T-cell factor 4 (TCF4; 602228), causing increased transcriptional activation of unknown genes. He et al. (1998) showed that the MYC oncogene is a target in this signaling pathway. They showed that expression of MYC is repressed by wildtype APC and activated by beta-catenin, and that effects are mediated through TCF4 binding sites in the MYC promoter.

Wu et al. (1999) demonstrated that the MYC protein represses the expression of ferritin-H (134770), which sequesters intracellular iron, and stimulates the expression of iron regulatory protein-2 (IRP2; 147582), which increases the intracellular iron pool. Downregulation of ferritin-H expression was required for cell transformation by c-myc. Wu et al. (1999) further demonstrated that the downregulation of ferritin-H expression was independent of c-myc-induced changes in cell cycle activity. The authors concluded that this function for c-myc is consistent with observations that iron chelation leads to growth arrest.

Wu et al. (1999) demonstrated direct activation of telomerase by MYC. Telomerase is the ribonuclear protein complex expressed in proliferating and transformed cells, in which it preserves chromosomal integrity by maintaining telomere length. MYC activates telomerase by inducing expression of its catalytic subunit, telomerase-reverse transcriptase (TERT; 187270). Telomerase complex activity is dependent on TERT, a specialized type of reverse transcriptase. Wu et al. (1999) showed that TERT is a target of MYC activity and identified a pathway linking cell proliferation and chromosome integrity in normal and neoplastic cells.

Wang et al. (2000) demonstrated that TERT-driven cell proliferation is not genoprotective because it is associated with activation of the MYC oncogene. Human mammary epithelial cells, which normally stop dividing in culture at 55 to 60 population doublings (PDs), were infected with human TERT retrovirus at PD40 and maintained until PD250. Wang et al. (2000) then tested whether telomerase activity was essential for the immortalized phenotype by excising the TERT retrovirus at PD150 using Cre recombinase. The resulting cells were maintained for at least another 20 population doublings, and no decline in growth rates in either pooled cells or individual clones was observed. Ectopic expression of MYC was found to be upregulated between 107 and 135 population doublings. Wang et al. (2000) suggested that under standard culture conditions, extension of life span by telomerase selects for MYC overexpression in human mammary epithelial cells.

Ma et al. (2000) analyzed the murine c-Myc promoter response to glucocorticoid and identified a novel glucocorticoid response element that does not conform to the consensus glucocorticoid receptor-binding sequence. Glucocorticoids activated c-Myc/reporter constructs that contained this element. Deletion of these sequences from the c-Myc promoter increased basal activity of the promoter and blocked glucocorticoid induction. Footprinting analysis suggested that a cellular repressor also binds to this element. Ma et al. (2000) concluded that the glucocorticoid receptor binds to the c-Myc promoter in competition with this protein, which is a repressor of transcription.

MYC induces transcription of the E2F1 (189971), E2F2 (600426), and E2F3 (600427) genes. Using primary mouse embryo fibroblasts deleted for individual E2f genes, Leone et al. (2001) showed that MYC-induced S phase and apoptosis requires distinct E2F activities. The ability of Myc to induce S phase was impaired in the absence of either E2f2 or E2f3 but not E2f1 or E2f4 (600659). In contrast, the ability of Myc to induce apoptosis was markedly reduced in cells deleted for E2f1 but not E2f2 or E2f3. The authors proposed that the induction of specific E2F activities is an essential component in the MYC pathways that control cell proliferation and cell fate decisions.

Feng et al. (2002) showed that MYC physically interacts with SMAD2 (601366) and SMAD3 (603109), 2 specific signal transducers involved in TGF-beta (190180) signaling. Through its direct interaction with SMADs, MYC binds to the SP1 (189906)-SMAD complex on the promoter of the p15(INK4B) gene (600431), thereby inhibiting the TGF-beta-induced transcriptional activity of SP1 and SMAD/SP1-dependent transcription of the p15(INK4B) gene. The oncogenic MYC promotes cell growth and cancer development partly by inhibiting the growth inhibitory functions of SMADs. Note that an Expression of Concern and an Editorial Note were published for the article by Feng et al. (2002).

To identify target genes of MYC, Menssen and Hermeking (2002) performed serial analysis of gene expression (SAGE) after adenoviral expression of MYC in primary human umbilical vein endothelial cells. Induction of 53 genes was confirmed using microarray analysis and quantitative RT-PCR. Among these genes was MetAP2, also called p67 (601870), which encodes an activator of translational initiation and represents a validated target for inhibition of neovascularization. Furthermore, MYC induced 3 cell cycle regulatory genes and 3 DNA repair genes, suggesting that MYC couples DNA replication to processes preserving the integrity of the genome. MNT (603039), a MAX-binding antagonist of MYC function, was upregulated, implying a negative feedback loop. In vivo promoter occupancy by MYC was detected by chromatin immunoprecipitation for at least 5 genes, showing that they are direct MYC targets. The authors suggested that the MYC-regulated genes identified by this study define a set of bona fide MYC targets and may have potential therapeutic value for inhibition of cancer cell proliferation, tumor vascularization, and restenosis.

Levens (2002) discussed and diagrammed the complex web of MYC-related pathways involved in growth, proliferation, and apoptosis.

Vafa et al. (2002) showed that brief MYC activation can induce DNA damage prior to S phase in normal human fibroblasts. Damage correlated with induction of reactive oxygen species (ROS) without induction of apoptosis. Deregulated MYC partially disabled the p53 (191170)-mediated DNA damage response, enabling cells with damaged genomes to enter the cycle, resulting in poor clonogenic survival. An antioxidant reduced ROS, decreased DNA damage and p53 activation, and improved survival. The authors proposed that oncogene activation can induce DNA damage and override damage controls, thereby accelerating tumor progression via genetic instability.

Activation of the tumor suppressor p53 by DNA damage induces either cell cycle arrest or apoptotic cell death. Seoane et al. (2002) demonstrated that MYC is a principal determinant of this choice. MYC is directly recruited to the p21(CIP1) (116899) promoter by the DNA-binding protein MIZ1 (604084). This interaction blocks p21(CIP1) induction by p53 and other activators. As a result MYC switches, from cytostatic to apoptotic, the p53-dependent response of colon cancer cells to DNA damage. MYC does not modify the ability of p53 to bind to the p21(CIP1) or PUMA (605854) promoters, but selectively inhibits bound p53 from activating p21(CIP1) transcription. By inhibiting p21(CIP1) expression MYC favors the initiation of apoptosis, thereby influencing the outcome of a p53 response in favor of cell death.

Herold et al. (2002) showed that transactivation by MIZ1 is negatively regulated by association with topoisomerase II-binding protein (TOPBP1; 607760). Ultraviolet (UV) irradiation downregulated expression of TOPBP1 and released MIZ1. MIZ1 bound to the p21CIP1 core promoter in vivo and was required for upregulation of p21CIP1 upon UV irradiation. Using both Myc -/- cells and a point mutant of MYC that is deficient in MIZ1-dependent repression, Herold et al. (2002) showed that MYC negatively regulates transcription of p21CIP1 upon UV irradiation and facilitates recovery from UV-induced cell cycle arrest through binding to MIZ1.

Gomez-Roman et al. (2003) demonstrated that c-MYC binds to transcription factor IIIB (see 604902), an RNA polymerase III (pol III)-specific general transcription factor, and directly activates pol III transcription. Chromatin immunoprecipitation revealed that endogenous c-MYC is present at tRNA and 5S rRNA genes in cultured mammalian cells. Gomez-Roman et al. (2003) concluded that activation of pol III may have a role in the ability of c-MYC to stimulate cell growth.

In mouse embryo fibroblasts, Qi et al. (2004) showed that p19(Arf) (CDKN2A; 600160) can inhibit c-Myc by a unique and direct mechanism that is independent of p53 (191170). When c-Myc increased, p19(Arf) bound with c-Myc and dramatically blocked c-Myc's ability to activate transcription and induce hyperproliferation and transformation. In contrast, c-Myc's ability to repress transcription was unaffected by p19(Arf), and c-Myc-mediated apoptosis was enhanced. These differential effects of p19(Arf) on c-Myc function suggested that separate molecular mechanisms mediate c-Myc-induced hyperproliferation and apoptosis. This direct feedback mechanism represents a p53-independent checkpoint to prevent c-Myc-mediated tumorigenesis.

Hemann et al. (2005) reported that 2 common mutant MYC alleles derived from human Burkitt lymphoma (113970) uncouple proliferation from apoptosis and, as a result, are more effective than wildtype MYC at promoting B-cell lymphomagenesis in mice. Mutant MYC proteins retain their ability to stimulate proliferation and activate p53, but are defective at promoting apoptosis due to a failure to induce the BH3-only protein BIM (603827) and effectively inhibit BCL2 (151430). Disruption of apoptosis through enforced expression of BCL2, or loss of either BIM or p53 function, enables wildtype MYC to produce lymphomas as efficiently as mutant MYC. Hemann et al. (2005) concluded that their data show how parallel apoptotic pathways act together to suppress MYC-induced transformation, and how mutant MYC proteins, by selectively disabling a p53-independent pathway, enable tumor cells to evade p53 action during lymphomagenesis.

He et al. (2005) compared B-cell lymphoma samples and cell lines to normal tissues, and found that the levels of the primary or mature microRNAs derived from the miR17-92 locus (609416) within C13ORF25 (609415) were often substantially increased in the cancers. Enforced expression of the miR17-92 cluster acted with c-Myc expression to accelerate tumor development in a mouse B-cell lymphoma model. Tumors derived from hematopoietic stem cells expressing a subset of the miR17-92 cluster and c-Myc could be distinguished by an absence of apoptosis that was otherwise prevalent in c-Myc-induced lymphomas. He et al. (2005) concluded that noncoding RNAs, specifically microRNAs, can modulate tumor formation, and implicated the miR17-92 cluster as a potential human oncogene.

O'Donnell et al. (2005) showed that c-Myc activates expression of a cluster of 6 miRNAs on human chromosome 13 (see 609415). Chromatin immunoprecipitation experiments showed that c-Myc binds directly to this locus. The transcription factor E2F1 (189971) is an additional target of c-Myc that promotes cell cycle progression. O'Donnell et al. (2005) found that expression of E2F1 is negatively regulated by 2 miRNAs in this cluster, miR17-5p (609416) and miR20a (609420). O'Donnell et al. (2005) concluded that their findings expand the known classes of transcripts within the c-Myc target gene network, and reveal a mechanism through which c-Myc simultaneously activates E2F1 transcription and limits its translation, allowing a tightly controlled proliferative signal.

Noubissi et al. (2006) demonstrated that CRDBP (IGF2BP1; 608288) is essential for the induction of both BTRCP1 (603482) and c-Myc by beta-catenin (see 116806) signaling in colorectal cancer cells. Noubissi et al. (2006) concluded that high levels of CRDBP that are found in primary human colorectal tumors exhibiting active beta-catenin/Tcf signaling implicates CRDBP induction in the upregulation of BTRCP1, in the activation of dimeric transcription factor NF-kappa-B (see 164011), and in the suppression of apoptosis in these cancers.

By database analysis, Huang et al. (2020) found that the long noncoding RNA (lncRNA) SNHG11 (619494) was highly expressed in various human cancers, especially in CRC, and that upregulation of SNHG11 was associated with poor prognosis in CRC patients. Ectopic overexpression of SNHG11 enhanced proliferation of SW480 and LoVo human CRC cells, whereas SNHG11 downregulation inhibited their proliferation. SNHG11 interacted directly with the mRNA-binding protein IGF2BP1 to enhance binding between IGF2BP1 and MYC mRNA, a target of IGF2BP1. Consequently, MYC mRNA expression was stabilized, leading to upregulation of MYC target genes and promotion of cell proliferation in CRC. Further analysis demonstrated that SNHG11 was a direct target of MYC and that upregulation of MYC by SNHG11 in turn transcriptionally upregulated SNHG11.

By examining gene expression profiles, Palomero et al. (2006) found that NOTCH (190198) and MYC regulate 2 interconnected transcriptional programs containing common target genes that regulate cell growth in primary human T-cell lymphoblastic leukemias.

Dominguez-Sola et al. (2007) showed that c-Myc has a direct role in the control of DNA replication. c-Myc interacts with the prereplicative complex and localizes to early sites of DNA synthesis. Depletion of c-Myc from mammalian (human and mouse) cells as well as from Xenopus cell-free extracts, which are devoid of RNA transcription, demonstrated a nontranscriptional role for c-Myc in the initiation of DNA replication. Dominguez-Sola et al. (2007) found that overexpression of c-Myc caused increased replication origin activity with subsequent DNA damage and checkpoint activation.

Induced pluripotent stem (iPS) cells can be generated from mouse fibroblasts by retrovirus-mediated introduction of 4 transcription factors, Oct3/4 (164177), Sox2 (184429), c-Myc, and Klf4 (602253), and subsequent selection for Fbx15 (609093) expression (Takahashi and Yamanaka, 2006). These iPS cells, hereafter called Fbx15 iPS cells, are similar to embryonic stem (ES) cells in morphology, proliferation, and teratoma formation; however, they are different with regard to gene expression and DNA methylation patterns, and fail to produce adult chimeras. Okita et al. (2007) showed that selection for Nanog (607937) expression results in germline-competent iPS cells with increased ES cell-like gene expression and DNA methylation patterns compared with Fbx15 iPS cells. The 4 transgenes were strongly silenced in Nanog iPS cells. Okita et al. (2007) obtained adult chimeras from 7 Nanog iPS cell clones, with one clone being transmitted through the germline to the next generation. Approximately 20% of the offspring developed tumors attributable to reactivation of the c-Myc transgene. Okita et al. (2007) concluded that iPS cells competent for germline chimeras can be obtained from fibroblasts, but retroviral introduction of c-Myc should be avoided for clinical application.

Wernig et al. (2007) independently demonstrated that the transcription factors Oct4, Sox2, c-Myc, and Klf4 can induce epigenetic reprogramming of a somatic genome to an embryonic pluripotent state.

Using Oct4, Sox2, Klf4, and Myc, Park et al. (2008) derived iPS cells from fetal, neonatal, and adult human primary cells, including dermal fibroblasts isolated from a skin biopsy of a healthy research subject. Human iPS cells resemble embryonic stem cells in morphology and gene expression and in the capacity to form teratomas in immune-deficient mice. Park et al. (2008) concluded that defined factors can reprogram human cells to pluripotency, and they established a method whereby patient-specific cells might be established in culture.

Kim et al. (2008) showed that adult mouse neural stem cells express higher endogenous levels of Sox2 and c-Myc than embryonic stem cells and that exogenous Oct4 together with either Klf4 (602253) or c-Myc is sufficient to generate induced pluripotent stem (iPS) cells from neural stem cells. These 2-factor iPS cells are similar to embryonic stem cells at the molecular level, contribute to development of the germ line, and form chimeras. Kim et al. (2008) proposed that, in inducing pluripotency, the number of reprogramming factors can be reduced when using somatic cells that endogenously express appropriate levels of complementing factors.

Stadtfeld et al. (2008) generated mouse iPS cells from fibroblasts and liver cells by using nonintegrating adenoviruses transiently expressing Oct4, Sox2, Klf4, and c-Myc. These adenoviral iPS cells showed DNA demethylation characteristic of reprogrammed cells, expressed endogenous pluripotency genes, formed teratomas, and contributed to multiple tissues, including the germ cell line, in chimeric mice. Stadtfeld et al. (2008) concluded that their results provided strong evidence that insertional mutagenesis is not required for in vitro reprogramming.

Okita et al. (2008) independently reported the generation of mouse iPS cells without viral vectors. Repeated transfection of 2 expression plasmids, one containing the cDNAs of Oct3/4, Sox2, and Klf4 and the other containing the c-Myc cDNA, into mouse embryonic fibroblasts resulted in iPS cells without evidence of plasmid integration, which produced teratomas when transplanted into mice and contributed to adult chimeras. Okita et al. (2008) concluded that the production of virus-free iPS cells, albeit from embryonic fibroblasts, addresses a critical safety concern for potential use of iPS cells in regenerative medicine.

Hanna et al. (2009) demonstrated that the reprogramming by Oct4, Sox2, Klf4, and Myc transcription factors is a continuous stochastic process where almost all mouse donor cells eventually give rise to iPS cells on continued growth and transcription factor expression. Additional inhibition of the p53 (191170)/p21 (116899) pathway or overexpression of Lin28 (611043) increased the cell division rate and resulted in an accelerated kinetics of iPS cell formation that was directly proportional to the increase in cell proliferation. In contrast, Nanog overexpression accelerated reprogramming in a predominantly cell division rate-independent manner. Quantitative analyses defined distinct cell division rate-dependent and -independent modes for accelerating the stochastic course of reprogramming, and suggested that the number of cell divisions is a key parameter driving epigenetic reprogramming to pluripotency.

Sotelo et al. (2010) identified a highly conserved enhancer element, designated enhancer E, over 340 kb telomeric to the MYC gene. Reporter gene assays and chromatin immunoprecipitation analysis revealed that beta-catenin/TCF4 interacted with enhancer E and activated expression of a MYC reporter. Chromosome conformation capture assays suggested formation of long-range DNA looping between the enhancer and the MYC promoter.

Using a yeast 2-hybrid screen, Escamilla-Powers et al. (2010) found that human HBP1 (616714) bound the MYC transactivation domain. MYC bound the C terminus of HBP1. Knockdown of HBP1 increased MYC transactivational activity.

Using human cell lines, Liao and Lu (2011) found that serum-induced MYC expression upregulated expression of the miRNA MIR185-3p (615576) via an E box in the MIR185 promoter region. MIR185-3p directly downregulated MYC expression in a negative-feedback loop, reducing expression of the MYC target E2F2 (600426) and inhibiting cell proliferation. However, unlike MIR24 (see 609705), which downregulates MYC expression by binding to a target site in the MYC 3-prime UTR, MIR185-3p bound to a region of the MYC transcript that encodes the C-terminal domain and inhibited MYC translation.

By screening for short hairpin RNAs (shRNAs) that altered the fitness of mammary epithelial cells only in the presence of aberrant MYC, Kessler et al. (2012) identified the SUMO-activating enzymes SAE1 (613294) and SAE2 (UBA2; 613295) as MYC-synthetic lethal genes. Inactivation of SAE2 led to mitotic catastrophe and cell death upon MYC hyperactivation. SAE2 inhibition switched a MYC transcriptional subprogram from activated to repressed. A subset of sumoylation-dependent MYC switchers (SMS genes), including CASC5 (609173), BARD1 (601593), and CDC20 (603618), was required for mitotic spindle function and to support the MYC oncogenic program. Sae2 was required for growth of Myc-dependent tumors in mice. Transduction of MYC-dependent breast cancer cells with inducible SAE2 shRNA suggested that SAE2 was required for growth and fitness of these cell lines. Gene expression analysis of human breast cancers with hyperactive MYC suggested that low expression of SAE1 and SAE2 resulted in better metastasis-free survival. Kessler et al. (2012) proposed that altering distinct subprograms of MYC transcription, such as by SAE2 inactivation, may be a therapeutic strategy in MYC-driven cancers.

Claveria et al. (2013) established a method for inducing functional genetic mosaics in the mouse. Using the system, the authors showed that induction of a mosaic imbalance of Myc expression in the epiblast provokes the expansion of cells with higher Myc levels through the apoptotic elimination of cells with lower levels, without disrupting development. In contrast, homogeneous shifts in Myc levels did not affect epiblast cell viability, indicating that the observed competition results from comparison of relative Myc levels between epiblast cells. Claveria et al. (2013) found that during normal development, Myc levels are intrinsically heterogeneous among epiblast cells, and that endogenous cell competition refines the epiblast cell population through the elimination of cells with low relative Myc levels. Claveria et al. (2013) concluded that natural cell competition in the early mammalian embryo contributes to the selection of the epiblast cell pool.

Rais et al. (2013) showed that depleting MBD3 (603573), a core member of the MBD3/NURD (nucleosome remodeling and deacetylation) repressor complex, together with OSKM (OCT4, SOX2, KLF4, and MYC) transduction and reprogramming in naive pluripotency-promoting conditions, result in deterministic and synchronized iPS cell reprogramming (nearly 100% efficiency within 7 days from mouse and human cells). Rais et al. (2013) stated that their findings uncovered a dichotomous molecular function for the reprogramming factors, serving to reactivate endogenous pluripotency networks while simultaneously directly recruiting the MBD3/NURD repressor complex that potently restrains the reactivation of OSKM downstream target genes. Subsequently, the latter interactions, which are largely depleted during early preimplantation development in vivo, lead to a stochastic and protracted reprogramming trajectory toward pluripotency in vitro. Rais et al. (2013) concluded that their deterministic reprogramming approach offered a novel platform for the dissection of molecular dynamics leading to establishing pluripotency at unprecedented flexibility and resolution.

Koh et al. (2015) demonstrated that during lymphomagenesis in E-mu-myc transgenic mice, MYC directly upregulates the transcription of the core small nuclear ribonucleoprotein particle assembly genes, including Prmt5 (604045), an arginine methyltransferase that methylates Sm proteins. This coordinated regulatory effect is critical for the core biogenesis of small nuclear ribonucleoprotein particles, effective pre-mRNA splicing, cell survival, and proliferation. Koh et al. (2015) suggested that their results demonstrated that MYC maintains the splicing fidelity of exons with a weak 5-prime donor site. Additionally, the authors identified pre-mRNAs that are particularly sensitive to the perturbation of the MYC-PRMT5 axis, resulting in either intron retention (e.g., Dvl1, 601365) or exon skipping (e.g., Atr, 601215 or Ep400, 606265). Using antisense oligonucleotides, Koh et al. (2015) demonstrated the contribution of these splicing defects to the antiproliferative/apoptotic phenotype observed in PRMT5-depleted E-mu-myc B cells. The authors concluded that, in addition to its well-documented oncogenic functions in transcription and translation, MYC also safeguards proper pre-mRNA splicing as an essential step in lymphomagenesis.

Casey et al. (2016) demonstrated that MYC regulates the expression of 2 immune checkpoint proteins on the tumor cell surface: the innate immune regulator cluster of differentiation-47 (CD47; 601028) and the adaptive immune checkpoint programmed death ligand-1 (PDL1; 605402). Suppression of MYC in mouse tumors and human tumor cells caused a reduction in the levels of CD47 and PDL1 mRNA and protein. MYC was found to bind directly to the promoters of the Cd47 and Pdl1 genes. MYC inactivation in mouse tumors downregulated CD47 and PDL1 expression and enhanced the antitumor immune response. In contrast, when MYC was inactivated in tumors with enforced expression of CD47 or PDL1, the immune response was suppressed, and tumors continued to grow. Thus, Casey et al. (2016) concluded that MYC appears to initiate and maintain tumorigenesis, in part through the modulation of immune regulatory molecules.

Fulco et al. (2016) presented a high-throughput approach that uses clustered regularly interspaced short palindromic repeats (CRISPR) interference (CRISPRi) to discover regulatory elements and identify their target genes. Fulco et al. (2016) assessed more than 1 megabase of sequence in the vicinity of 2 essential transcription factors, MYC and GATA1 (305371), and identified 9 distal enhancers that control gene expression and cellular proliferation. Quantitative features of chromatin state and chromosome conformation distinguish the 7 enhancers that regulate MYC from other elements that do not, suggesting a strategy for predicting enhancer-promoter connectivity. Fulco et al. (2016) suggested that this CRISPRi-based approach could be applied to dissect transcriptional networks and interpret the contributions of noncoding genetic variation to human disease.

Bahr et al. (2018) showed that an evolutionarily conserved region located 1.7 megabases downstream of the Myc gene that had previously been labeled as a superenhancer is essential for the regulation of Myc expression levels in both normal hematopoietic and leukemic stem cell hierarchies in mice and humans. Deletion of this region in mice leads to a complete loss of Myc expression in hematopoietic stem cells and progenitors. This caused an accumulation of differentiation-arrested multipotent progenitors and loss of myeloid and B cells, mimicking the phenotype caused by Mx1-Cre-mediated conditional deletion of the Myc gene in hematopoietic stem cells. This superenhancer comprises multiple enhancer modules with selective activity that recruits a compendium of transcription factors, including GFI1B (604383), RUNX1 (151385), and MYB (189990). Analysis of mice carrying deletions of individual enhancer modules suggested that specific Myc expression levels throughout most of the hematopoietic hierarchy are controlled by the combinatorial and additive activity of individual enhancer modules, which collectively function as a 'blood enhancer cluster' (BENC). Bahr et al. (2018) showed that BENC is also essential for the maintenance of MLL-AF9-driven leukemia in mice. Furthermore, a BENC module, which controls Myc expression in mouse hematopoietic stem cells and progenitors, showed increased chromatin accessibility in human acute myeloid leukemia stem cells compared to blasts. This difference correlates with MYC expression and patient outcome. Bahr et al. (2018) proposed that clusters of enhancers, such as BENC, form highly combinatorial systems that allow precise control of gene expression across normal cellular hierarchies and which also can be hijacked in malignancies.

Using immunoprecipitation followed by mass spectrometry analysis, Lee et al. (2019) identified the HECT-type E3 ubiquitin ligase WWP1 (602307) as a physical PTEN (601728) interactor and found that WWP1 specifically triggers nondegradative K27-linked polyubiquitination of PTEN to suppress its dimerization, membrane recruitment, and tumor suppressive functions both in vivo and in vitro. WWP1 is genetically amplified and frequently overexpressed in multiple cancers, including those of prostate, breast, and liver, which lead to pleiotropic inactivation of PTEN. Lee et al. (2019) found that WWP1 may be transcriptionally activated by the MYC protooncogene and that genetic depletion of Wwp1 in both Myc- driven mouse models of prostate cancer in vivo and cancer cells in vitro reactivates PTEN function, leading to inhibition of the PI3K-AKT pathway and MYC-driven tumorigenesis. Structural simulation and biochemical analyses showed that indole-3-carbinol (I3C), a derivative of cruciferous vegetables, was a natural and potent WWP1 inhibitor. Lee et al. (2019) concluded that the MYC-WWP1 axis is a fundamental and evolutionary conserved regulatory pathway for PTEN and PI3K signaling.

MYC Alterations in Cancer

Collins and Groudine (1982) found that the normal human homolog of the avian myc oncogene was present in multiple copies in the DNA of a malignant promyelocyte cell line derived from the peripheral blood of a patient with acute promyelocytic leukemia. Other human oncogenes were not amplified.

Yokota et al. (1986) concluded that alterations are found in oncogenes MYC, HRAS, or MYB in more than one-third of human solid tumors. Amplification of MYC was found in advanced widespread tumors and in aggressive primary tumors. Apparent allelic deletions of HRAS and MYB could be correlated with progression and metastasis of carcinomas and sarcomas.

Morse et al. (1988) found rearrangement of MYC in a breast carcinoma due to insertion of a LINE-1 element.

Specific types of human papillomavirus (HPV), mostly HPV type 16 (HPV16) and type 18 (HPV18), are associated with genital carcinomas such as those of the cervix and their noninvasive precursors (167959, 167960). In intraepithelial neoplasia, HPV DNA is detected most commonly as episomal molecules, whereas it is found integrated in the cell genome in the majority of invasive carcinomas. By chromosomal in situ hybridization experiments, Couturier et al. (1991) determined the localization of integrated HPV16 or HPV18 genomes in genital cancers. In 3 cancers, HPV sequences were located in band 8q24.1, which contains the MYC gene, and in 1 cancer, HPV sequences were located in band 2p24, which contains the NMYC gene (164840). In 3 of the 4 cases, the protooncogene located near integrated viral sequences was found to be structurally altered and/or overexpressed.

Ioannidis et al. (2003) found copy number gains encompassing the MYC gene at chromosome 8q24 in 29 of 60 (48.3%) breast carcinomas examined. A highly significant association was found between 8q24 copy number gains and advanced tumor grade (grade I/II vs grade II, p of 0.006), and a statistically significant association was observed with the mitotic index score (1 or 2 vs 3, p of 0.038). Statistically significant higher levels of MYC mRNA were observed only in samples showing 8q24 copy number gains (p of 0.022).

Double minutes (dmin), the cytogenetic hallmark of genomic amplification, are found in 1% of karyotypically abnormal acute myeloid leukemias (AML; 601626) and myelodysplastic syndromes (MDS). The MYC gene is amplified in the majority of the cases and is generally assumed to be the target gene. Storlazzi et al. (2004) studied 5 AML cases and 1 MDS case with MYC-containing dmin. Detailed FISH analyses identified a common 4.3-Mb amplicon harboring 8 genes, including MYC and C8FW (609461). The corresponding region was deleted in one of the chromosome 8 homologs in 5 of the 6 cases, suggesting that the dmin originated through extra replication (or loop-formation)-excision-amplification. Northern blot analysis revealed that MYC was not overexpressed. Instead, the C8FW gene, encoding a phosphoprotein regulated by mitogenic pathways, displayed increased expression. These results excluded MYC as the target gene; the authors hypothesized that overexpression of C8FW may be the functionally important consequence of 8q24 amplicons in AML and MDS.

Heim and Mitelman (1987) counted a total of 83 bands that have been found to be specifically involved in primary structural chromosome rearrangements in human cancer. They compared the distribution of these breakpoints with the chromosomal sites of 26 cellular oncogenes, including MYC, which had to that time been mapped to individual bands in the human genome. Nineteen of the 26 oncogenes were located in cancer-associated bands. This clustering is statistically significant (p = 0.0000012). They pointed out that cancer may be inflated by errors of karyotype interpretation. Furthermore, it appears that only 1 of the 2 breakpoints in cancer-specific translocations is the site of an oncogene, so that the number of cancer-associated breakpoints that are found to contain oncogenes should theoretically approach 50% of the total. Mitelman (1985) provided a useful catalog of chromosome aberrations in cancer. Duesberg (1987) suggested that cellular cancer genes, such as MYC, are not activated oncogenes but rather the result of rare truncations and illegitimate recombinations that alter the germline configuration of cellular genes. See review by Cole (1986).

Barna et al. (2008) intercrossed Myc transgenic mice, in which Myc is overexpressed in the B-cell compartment (termed E(mu)-Myc/+) with L24 (RPL24; 604180) heterozygous mice, which have overall decreased protein synthesis. By lowering the threshold of protein production in L24 heterozygote mice, the increased protein synthesis rates and cell size in the E(mu)-Myc heterozygote cells were restored to normal levels in the compound heterozygote mice. This effect suppressed the oncogenic potential of Myc in this context. Barna et al. (2008) concluded that the ability of Myc to increase protein synthesis directly augments cell size and is sufficient to accelerate cell cycle progression independently of known cell cycle targets transcriptionally regulated by Myc. In addition, when protein synthesis is restored to normal levels, Myc-overexpressing precancerous cells are more efficiently eliminated by programmed cell death. Barna et al. (2008) suggested that their findings revealed a mechanism that links increases in general protein synthesis rates downstream of an oncogenic signal to a specific molecular impairment in the modality of translation initiation used to regulate the expression of selective mRNAs. Barna et al. (2008) showed that an aberrant increase in cap-dependent translation downstream of Myc hyperactivation specifically impairs the translational switch to internal ribosomal entry site (IRES)-dependent translation that is required for accurate mitotic progression. Failure of this translational switch results in reduced mitotic-specific expression of the endogenous IRES-dependent form of Cdk11 (176873), which leads to cytokinesis defects and is associated with increased centrosome numbers and genome instability in E(mu)-Myc/+ mice. When accurate translational control is reestablished in E(mu)-Myc/+ mice, genome instability is suppressed.

Altered glucose metabolism in cancer cells is termed the Warburg effect, which describes the propensity of most cancer cells to take up glucose avidly and convert it primarily to lactate, despite available oxygen. Cancer cells also depend on continued mitochondrial function for metabolism, specifically glutaminolysis that catabolizes glutamine to generate ATP and lactate. Glutamine, which is highly transported into proliferating cells, is a major source of energy and nitrogen for biosynthesis, and a carbon substrate for anabolic processes in cancer cells. Gao et al. (2009) reported that the c-Myc oncogenic transcription factor, which is known to regulate microRNAs and stimulate cell proliferation, transcriptionally represses miR23a (607962) and miR23b (610723), resulting in greater expression of their target protein, mitochondrial glutaminase (GLS; 138280), in human P-493 B lymphoma cells and PC3 prostate cancer cells. This effect leads to upregulation of glutamine catabolism. Glutaminase converts glutamine to glutamate, which is further catabolized through the tricarboxylic acid cycle for the production of ATP or serves as substrate for glutathione synthesis. Gao et al. (2009) concluded that the unique means by which Myc regulates glutaminase uncovers a previously unsuspected link between Myc regulation of microRNAs, glutamine metabolism, and energy and reactive oxygen species homeostasis.

Liu et al. (2012) showed in human and murine cell lines that oncogenic levels of MYC established a dependence on AMP-related kinase-5 (ARK5; 608130) for maintaining metabolic homeostasis and for cell survival. ARK5 is an upstream regulator of AMPK and limits protein synthesis via the mTOR complex-1 (see 601231) signaling pathway. ARK5 also maintains expression of mitochondrial respiratory chain complexes and respiratory capacity, which is required for efficient glutamine metabolism. Inhibition of ARK5 leads to a collapse of cellular ATP levels in cells expressing deregulated MYC, inducing multiple proapoptotic responses as a secondary consequence. Depletion of ARK5 prolonged survival in MYC-driven mouse models of hepatocellular carcinoma, demonstrating that targeting cellular energy homeostasis is a valid therapeutic strategy to eliminate tumor cells that express deregulated MYC.

Using chromosome engineering in mice, Tseng et al. (2014) showed that a single extra copy of either the Myc gene or the region encompassing Pvt1 (165140), Ccdc26 (613040), and Gsdmc (608384) fails to advance cancer measurably, whereas a single supernumerary segment encompassing all 4 genes successfully promotes cancer. Gain of PVT1 lncRNA expression was required for high MYC protein levels in 8q24-amplified human cancer cells. PVT1 RNA and MYC protein expression correlated in primary human tumors, and copy number of PVT1 was coincreased in more than 98% of MYC copy-increase cancers. Ablation of PVT1 from MYC-driven colon cancer cell line HCT116 diminished its tumorigenic potency. As MYC protein had been refractory to small-molecule inhibition, the dependence of high MYC protein levels on PVT1 lncRNA provided a therapeutic target.

Cho et al. (2018) found that CRISPR interference of the PVT1 promoter enhanced proliferation and competition in human breast cancer cells. Gene expression analysis showed that interference of the PVT1 promoter caused increased expression of MYC, which in turn promoted cell competition and proliferation in breast cancer cells in a PVT1 lncNA-independent manner. The PVT1 and MYC promoters, which are located 58 kb apart, competed for engagement with 4 intragenic enhancers in the PVT1 locus, thereby allowing the PVT1 promoter to suppress MYC transcription. This PVT1-MYC promoter competition was cell-type specific, and the dynamic interplay between PVT1 and MYC was coregulated through chromatin contacts. Studies in breast cancer cells demonstrated that regulation of PVT1 and MYC via promoter competition was bidirectional, as interference with the PVT1 promoter decreased MYC transcription, and interference with the MYC promoter increased PVT1 transcription. The authors measured chromatin accessibility, histone modification, and RNA transcripts in an allele-specific fashion in mouse cells and found that Pvt1 underwent developmentally regulated monoallelic expression, and that the Pvt1 promoter directly repressed Myc transcription only from the same chromosome via promoter competition.

Hsu et al. (2015) discovered that the spliceosome is a target of oncogenic stress in MYC-driven cancers. They identified BUD31 (603477) as a MYC-synthetic lethal gene in human mammary epithelial cells, and demonstrated that BUD31 is a component of the core spliceosome required for its assembly and catalytic activity. Core spliceosomal factors associated with BUD31 such as SF3B1 (605590) and U2AF1 (191317) are also required to tolerate oncogenic MYC. Notably, MYC hyperactivation induces an increase in total precursor mRNA synthesis, suggesting an increased burden on the core spliceosome to process pre-mRNA. In contrast to normal cells, partial inhibition of the spliceosome in MYC-hyperactivated cells leads to global intron retention, widespread defects in pre-mRNA maturation, and deregulation of many essential cell processes. Notably, genetic or pharmacologic inhibition of the spliceosome in vivo impairs survival, tumorigenicity, and metastatic proclivity of MYC-dependent breast cancers. Hsu et al. (2015) concluded that oncogenic MYC confers a collateral stress on splicing, and that components of the spliceosome may be therapeutic entry points for aggressive MYC-driven cancers.

▼ Biochemical Features

Nair and Burley (2003) determined the x-ray structures of the basic/helix-loop-helix/leucine zipper (bHLHZ) domains of MYC-MAX and MAD (600021)-MAX heterodimers bound to their common DNA target, the enhancer box (E box) hexanucleotide (5-prime-CACGTG-3-prime), at 1.9- and 2.0-angstrom resolution, respectively. E-box recognition by these 2 structurally similar transcription factor pairs determines whether a cell will divide and proliferate (MYC-MAX) or differentiate and become quiescent (MAD-MAX). Deregulation of MYC has been implicated in the development of many human cancers, including Burkitt lymphoma (113970), neuroblastomas, and small cell lung cancers. Both quasisymmetric heterodimers resemble the symmetric MAX homodimer, albeit with marked structural differences in the coiled-coil leucine zipper regions that explain preferential homo- and heteromeric dimerization of these 3 evolutionarily related DNA-binding proteins. The MYC-MAX heterodimer, but not its MAD-MAX counterpart, dimerizes to form a bivalent heterotetramer, explaining how MYC can upregulate expression of genes with promoters bearing widely separated E boxes.

▼ Cytogenetics

Translocations of MYC in Burkitt Lymphoma

Taub et al. (1982) found that in 2 Burkitt lymphoma (113970) cell lines, MYC was translocated into a DNA restriction fragment that also encoded the immunoglobulin mu chain gene (IGHM; 147020). In a mouse plasmacytoma, the MYC gene was translocated into the immunoglobulin alpha switch region.

Maguire et al. (1983) found that Burkitt and non-Burkitt lymphomas with either an 8;14 or an 8;22 translocation expressed 2- to 5-fold more MYC-specific RNA than B-cell lines without a translocation. Tumor cell lines of American origin with a translocation of either type expressed similar amounts of MYC-specific RNA. Tumor cell lines of African origin contained slightly higher levels of MYC-specific RNA than American lines, but the level did not correlate with absence or presence of Epstein-Barr virus (EBV). No MOS-related transcripts were found in these tumors. In Burkitt lymphomas bearing the 8;14 translocation, the MYC gene is translocated to a heavy chain switch recombination region (mu or alpha). See Adams et al. (1983).

The 14q marker in Burkitt lymphoma was first found by Manolov and Manolova (1972). Zech et al. (1976) showed that the extra chromosomal material joined to the end of one chromosome 14 was derived from the distal part of 8q. Bernheim et al. (1981) found either 2;8 or 8;22 translocation in about 10% of cases. The translocations separate the MYC gene from its normal promoter and 5-prime regulatory machinery, and place it under some regulatory element associated with the immunoglobulin gene. By hybrid cell studies of mouse plasmacytoma cells and Burkitt lymphoma cells, Nishikura et al. (1983) showed that cells containing the MYC gene on a translocation chromosome expressed high levels of human specific MYC transcripts, whereas hybrid cells containing the untranslocated MYC gene on the normal chromosome did not contain such MYC mRNA. Usually in t(8;14) translocations, the MYC gene is translocated to 14q. When the break occurs between the MYC first and second exons, both segments are transcriptionally active.

Croce et al. (1983) studied somatic cell hybrids between mouse myeloma cells and a Burkitt lymphoma human cell line with a t(8;22) chromosome translocation. The MYC gene was found to remain on chromosome 8q+; the normal chromosome 8 remains transcriptionally silent. The lambda constant region is translocated 3-prime to the MYC oncogene.

Translocations of MYC in Other Cancers

Alitalo et al. (1983) found that the MYC gene, which is involved by translocation in the generation of Burkitt lymphoma, was amplified, resulting in homogeneously staining chromosomal regions (HSRs), in a human neuroendocrine tumor cell line derived from a colon cancer. The HSR resided on a distorted X chromosome; amplification of MYC had been accompanied by translocation of the gene from its normal position on chromosome 8q24.

Erikson et al. (1986) studied 2 T-cell leukemias with a t(8;14)(q24;q11) chromosome translocation. In 1, rearrangement was detected in a region immediately 3-prime to the MYC locus. In the second, the breakpoint in the chromosome 14 occurred between genes for the variable and constant regions of the T-cell receptor alpha chain (TCRA; see 186880). The constant region locus had translocated to a region more than 38 kb 3-prime to the MYC gene, yet as was shown by the study of hybrids between the human cells and mouse cells, only the hybrids carrying the 8q+ chromosome expressed MYC. Thus, deregulation of the MYC locus can occur not only with translocation of the heavy chain locus or one or the other light chain locus to chromosome 8 but also with translocation of the TCRA locus.

Finger et al. (1986) found that in T-cell leukemias carrying a t(8;14)(q24;q11) translocation the TCRA gene cluster was implicated with translocation of a constant gene locus to a region 3-prime to the MYC oncogene. Thus, in this T-cell neoplasia, a mechanism operates comparable to that in B-cell neoplasms such as Burkitt lymphoma.

Formation of Translocations

Roix et al. (2003) examined the question of why translocations between chromosomes tend to recur at specific breakpoints in the genome. They provided evidence that higher-order spatial genome organization is a contributing factor in the formation of recurrent translocations. They showed that MYC, BCL (168461), and immunoglobulin loci, which are recurrently translocated in various B-cell lymphomas, are preferentially positioned in close spatial proximity relative to each other in normal B cells. Loci in spatial proximity are nonrandomly positioned toward the interior of the nucleus in normal B cells. This locus proximity is the consequence of higher-order genome structure rather than a property of individual genes. The results suggested that the formation of specific translocations in human lymphomas, and perhaps other tissues, is determined in part by higher-order spatial organization of the genome. Roix et al. (2003) first assessed the global nuclear organization of translocation-prone genes by localizing them using fluorescence in situ hybridization. The preferred positioning they found was statistically distinct from a uniform random distribution. They then measured the physical distance between MYC and its various translocation partners in karyotypically normal cells and compared their physical proximity with the clinically observed frequencies of translocation. They found that MYC was separated from its 2 most frequent translocation partners, IgH (see 147100) and IgL (147220), by 40.7% and 41.0% of the nuclear diameter, respectively, whereas its separation from its rare translocation partner, IgK (147200), was 47.1%. This last value was similar to that observed for a negative control locus, TGFBR2 (190182), which had never been reported to translocate with MYC; its mean separation was 49.4% of the nuclear diameter.

▼ Molecular Genetics

Contrary to the previous belief that MYC is wildtype in both types of tumors, Bhatia et al. (1993) found that 65% of 57 Burkitt lymphomas and 30% of 10 mouse plasmacytomas exhibited at least 1 amino acid substitution (see, e.g., 190080.0001-190080.0004). These mutations were apparently homozygous in all Burkitt lymphoma cell lines tested and in 2 tumor biopsies, implying that the mutations often occur before MYC/Ig (see 147220) translocation. In the mouse plasmacytomas, only the mutant myc allele was expressed, indicating a functional homozygosity with occurrence of mutations at the translocation. Many of the observed mutations were clustered in regions associated with transcriptional activation and apoptosis, and in the Burkitt lymphomas, they frequently occurred at sites of phosphorylation, suggesting that the mutations had a pathogenetic role. Most of the mutations observed were clearly not polymorphisms, for reasons in addition to the large number of different mutations observed: (1) a high proportion were missense mutations; (2) most tumors contained multiple mutations; and (3) each tumor had a unique pattern of mutations.

In addition to immunoglobulin V genes, the 5-prime sequences of BCL6 (109565) and FAS (TNFRSF6; 134637) are mutated in normal germinal center B lymphocytes. Genomic instability promotes tumorigenesis through defective chromosome segregation and DNA mismatch repair inactivation. By screening 18 loci for mutations, Pasqualucci et al. (2001) identified changes in the germline sequences of PIM1 (164960), MYC, ARHH (602037), and/or PAX5 (167414), in addition to BCL6, in a majority of diffuse large-cell lymphomas (DLCLs; see 601889). No mutations in PIM1, MYC, ARHH, and PAX5 were detected in germinal-center lymphocytes, naive B cells, or B-cell malignancies other than DLCLs. MYC mutations, which were found in 32% of DLCLs, were located downstream of the major P1/P2 promoters in exon 1 or downstream of the minor P3 promoter in exon 2. FISH analysis indicated that hypermutation in these genes is not due to chromosomal translocation, as seen in Burkitt lymphoma (113970). Chromosomal translocation, however, may be an outcome of hypermutation. Specific features of the hypermutation process, including the predominance of single nucleotide substitutions with occasional deletions or duplications, a preference for transitions over transversions, and a specific motif targeting RGYW, were recognizable in each of the hypermutated loci. Pasqualucci et al. (2001) proposed that aberrant hypermutation of regulatory and coding sequences of genes that do not represent physiologic targets may provide the basis for DLCL pathogenesis and explain its phenotypic and clinical heterogeneity. This hypermutation malfunction is unlikely to be due to defective DNA mismatch repair and does not appear to involve activation-induced deaminase (AICDA; 605257)

Sotelo et al. (2010) noted that rs6983267, which is located within enhancer E over 340 kb telomeric to MYC, is strongly associated with susceptibility to colorectal cancer (CRCS2; 611469) and hereditary prostate cancer (HPC10; 611100). The T allele of rs6983267 consistently stimulated activity of a MYC reporter to a greater extent than the G allele in both the presence and absence of beta-catenin/TCF4. The effect of rs6983267 was not large, but it was highly reproducible, with p less than 0.0022.

▼ Evolution

Sequences of the MYC oncogene have been highly conserved throughout evolution, from Drosophila to vertebrates (Shilo and Weinberg, 1981).

Atchley and Fitch (1995) described phylogenetic analyses for 45 MYC protein sequences. A gene duplication early in vertebrate evolution produced the c-myc lineage and another lineage that later gave rise to the N- and L-myc lineages by another gene duplication. Evolutionary divergence in the MYC gene family corresponded closely to the known branching order of the major vertebrate groups. The closely related dimerization partner protein MAX exhibited significantly less variability than MYC. Atchley and Fitch (1995) suggested a reduced variability in MAX stems from natural selection acting to preserve dimerization capability with products of MYC and related genes.

▼ Animal Model

Trumpp et al. (2001) reported the generation of an allelic series of mice in which Myc expression is incrementally reduced to zero. Fibroblasts from these mice showed reduced proliferation, and after complete loss of Myc function they exited the cell cycle. Trumpp et al. (2001) showed that Myc activity is not needed for cellular growth but does determine the percentage of activated T cells that reenter the cell cycle. In vivo, reduction of Myc levels resulted in reduced body mass owing to multiorgan hypoplasia, in contrast to Drosophila dmyc mutants, which are smaller as a result of hypotrophy. Trumpp et al. (2001) found that dmyc substitutes for Myc in fibroblasts, indicating they have similar biologic activities. Trumpp et al. (2001) concluded that there may be fundamental differences in the mechanisms by which mammals and insects control body size, and proposed that in mammals MYC controls the decision to divide or not to divide and thereby functions as a crucial mediator of signals that determine organ and body size.

Baudino et al. (2002) stated that c-Myc-null mice die by embryonic day 10.5 with defects in growth and in cardiac and neural development. They determined that the lethality of c Myc-null embryos is associated with profound defects in vasculogenesis and primitive erythropoiesis, and compromised differentiation and growth of yolk sac and embryonic stem (ES) cells. Further, c-Myc expression was required for the expression of Vegf 192240, angiopoietin-2 (601922), thrombospondin-1 (188060), and angiopoietin-1 (601667), and expression of Vegf partially rescued the lethal defects. ES cells from c-Myc-null animals were impaired in their ability to form tumors in immune-compromised mice, and the small tumors that sometimes developed were poorly vascularized. Baudino et al. (2002) concluded that c-Myc is necessary for the angiogenic switch for the progression and metastasis of tumors, and that c-Myc promotes cell growth and transformation, as well as vascular and hematopoietic development, by functioning as a master regulator of angiogenic factors.

To explore the role of MYC in carcinogenesis, Pelengaris et al. (2002) developed a reversible transgenic mouse model of pancreatic beta-cell oncogenesis using a switchable form of the MYC protein. Activation of MYC in adult, mature beta cells induced uniform beta-cell proliferation but was accompanied by overwhelming apoptosis that rapidly eroded beta-cell mass. Thus, the oncogenic potential of MYC in beta cells was masked by apoptosis. Upon suppression of MYC-induced beta-cell apoptosis by coexpression of BCLXL (600039), MYC triggered rapid and uniform progression into angiogenic, invasive tumors. Subsequent MYC deactivation induced rapid regression associated with vascular degeneration and beta-cell apoptosis. These data indicated that highly complex neoplastic lesions can be both induced and maintained in vivo by a simple combination of 2 interlocking molecular lesions.

Jain et al. (2002) used a conditional transgenic mouse model for MYC-induced tumorigenesis to demonstrate that brief inactivation of MYC results in the sustained regression of tumors and the differentiation of osteogenic sarcoma cells into mature osteocytes. Subsequent reactivation of MYC did not restore the cells' malignant properties but instead induced apoptosis. Thus, Jain et al. (2002) concluded that brief MYC inactivation appears to cause epigenetic changes in tumor cells that render them insensitive to MYC-induced tumorigenesis. The authors raised the possibility that transient inactivation of MYC may be an effective therapy for certain cancers.

Langenau et al. (2003) described the induction of clonally derived T cell acute lymphoblastic leukemia in transgenic zebrafish expressing mouse c-Myc under the control of the zebrafish Rag2 promoter. Visualization of leukemic cells expressing a chimeric transgene encoding MYC fused to green fluorescent protein (GFP) revealed that leukemias arose in the thymus, spread locally into gill arches and retroorbital soft tissue, and then disseminated into skeletal muscle and abdominal organs. Leukemic cells homed back to the thymus in irradiated fish transplanted with GFP-labeled leukemic lymphoblasts. This transgenic model provided a platform for drug screens and genetic screens aimed at identifying mutations that suppress or enhance c-MYC-induced carcinogenesis.

Shachaf et al. (2004) generated transgenic mice that conditionally overexpressed Myc in liver cells. Upon Myc activation, all transgenic mice developed liver tumors and succumbed to invasive liver cancers. Myc inactivation induced tumor regression and the differentiation of tumor cells into normal liver cells. Their tumorigenic potential remained dormant as long as Myc remained inactive; Myc reactivation immediately restored their neoplastic properties.

Ruggero et al. (2004) generated transgenic mice that overexpressed translation initiation factor-4E (EIF4E; 133440) and observed a marked increase in tumorigenesis in the mice compared with their wildtype littermates. When the transgenic mice were intercrossed with a strain overexpressing Myc, the double-transgenic offspring developed lymphoma at a markedly accelerated rate. In the double-transgenic B cells, the ability of Myc to induce apoptosis was markedly reduced, and eif4e's induction of cellular senescence in vivo in splenic B cells was completely abrogated. Ruggero et al. (2004) concluded that EIF4E and MYC cooperate in inducing B-cell lymphomagenesis.

The normal function of MYC includes roles in the development, proliferation, and survival of lymphocytes. Refaeli et al. (2005) found that certain Myc transgenes elicited a murine lymphoma similar to Burkitt lymphoma. The lymphoma required cooperation between Myc and an autoantigenic stimulus of B cells, as well as a breach of immune tolerance. Refaeli et al. (2005) demonstrated that overexpression of Myc itself accounted for the breach of tolerance, which they attributed to the ability of Myc to serve as a surrogate for cytokines. Myc overexpression resulted in activated B cells that produced copious amounts of autoantibody and engendered immune complex disease in the kidney in response to a normally tolerated transgenic autoantigen.

To elucidate the role MYC has in the intestine after APC (611731) loss, Sansom et al. (2007) simultaneously deleted both Apc and Myc in the adult murine small intestine. They showed that loss of Myc rescued the phenotypes of perturbed differentiation, migration, proliferation, and apoptosis, which occur on deletion of Apc. Remarkably, this rescue occurred in the presence of high levels of nuclear beta-catenin. Array analysis revealed that Myc is required for the majority of Wnt (see 164820) target gene activation following Apc loss. Sansom et al. (2007) concluded that these data established MYC as the critical mediator of the early stages of neoplasia following APC loss.

Goga et al. (2007) examined the effects of inhibition of CDK1 (116940) in the context of different oncogenic signals. Cells transformed with MYC, but not cells transformed by a panel of other activated oncogenes, rapidly underwent apoptosis when treated with small-molecule CDK1 inhibitors. The inhibitor of apoptosis protein survivin (BIRC5; 603352), a non-CDK target, was required for the survival of cells overexpressing MYC. Inhibition of CDK1 rapidly downregulated survivin expression and induced MYC-dependent apoptosis. CDK1 inhibitor treatment of MYC-dependent mouse lymphoma and hepatoblastoma tumors decreased tumor growth and prolonged their survival.

Soucek et al. (2008) used a dominant-interfering Myc mutant to determine both the therapeutic impact and side effects of Myc inhibition in a preclinical mouse model of Ras (see 190020)-induced lung adenocarcinoma. They showed that Myc inhibition triggers rapid regression of incipient and established lung tumors, defining an unexpected role for endogenous Myc function in the maintenance of Ras-dependent tumors in vivo. Systemic Myc inhibition also exerts profound effects on normal regenerating tissues. However, these effects are well tolerated over extended periods and rapidly and completely reversible. Soucek et al. (2008) concluded that their data demonstrated the feasibility of targeting Myc, a common downstream conduit for many oncogenic signals, as an effective, efficient, and tumor-specific cancer therapy.

Hofmann et al. (2015) found that Myc haploinsufficient (Myc +/-) mice exhibited increased lifespan (10.7% for males, 20.9% for females, 15.1% overall). They showed resistance to several age-associated pathologies, including osteoporosis, cardiac fibrosis, and immunosenescence. They also appeared to be more active, with a higher metabolic rate and healthier lipid metabolism. Transcriptomic analysis revealed a gene expression signature enriched for metabolic and immune processes. The ancestral role of MYC as a regulator of ribosome biogenesis was reflected in reduced protein translation, which is inversely correlated with longevity. Hofmann et al. (2015) also observed changes in nutrient and energy sensing pathways, including reduced serum Igf1 (147440), increased AMPK activity (see 602739), and decreased Akt (164730), Tor (MTOR; 601231), and S6K (see 608938) activities. In contrast to observations in other longevity models, Myc +/- mice did not show improvements in stress management pathways.

▼ ALLELIC VARIANTS ( 4 Selected Examples):

Table View ClinVar

.0001 BURKITT LYMPHOMA, SOMATIC

MYC, PRO57SER

RCV000013402

Bhatia et al. (1993) found homozygosity for a CCC-to-TCC transition converting proline-57 to serine in Burkitt lymphoma-20 (DIF) (113970).

.0002 BURKITT LYMPHOMA, SOMATIC

MYC, ASN86THR

RCV000013403...

Bhatia et al. (1993) found homozygosity for an AAC-to-ACC transition converting asparagine-86 to threonine in Burkitt lymphoma-21 (DS179) (113970).

.0003 BURKITT LYMPHOMA, SOMATIC

MYC, GLU39ASP

RCV000013404

Bhatia et al. (1993) found homozygosity for a GAG-to-GAC transversion converting glutamic acid-39 to aspartic acid in Burkitt lymphoma-25 (JLP) (113970).

.0004 BURKITT LYMPHOMA, SOMATIC

MYC, PRO59ALA

RCV000013405...

Bhatia et al. (1993) found homozygosity for a CCG to GCG transversion converting proline-59 to alanine in Burkitt lymphoma-30 (WMN) (113970).

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Takahashi, E., Hori, T., O'Connell, P., Leppert, M., White, R. Mapping of the MYC gene to band 8q24.12-q24.13 by R-banding and distal to fra(8)(q24.11), FRA8E, by fluorescence in situ hybridization. Cytogenet. Cell Genet. 57: 109-111, 1991. [PubMed: 1914517, related citations] [Full Text]
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Tseng, Y.-Y., Moriarity, B. S., Gong, W., Akiyama, R., Tiwari, A., Kawakami, H., Ronning, P., Reuland, B., Guenther, K., Beadnell, T. C., Essig, J., Otto, G. M., O'Sullivan, M. G., Largaespada, D. A., Schwertfeger, K. L., Marahrens, Y., Kawakami, Y., Bagchi, A. PVT1 dependence in cancer with MYC copy-number increase. Nature 512: 82-86, 2014. [PubMed: 25043044, images, related citations] [Full Text]
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Contributors:

Bao Lige - updated : 08/19/2021

Ada Hamosh - updated : 06/10/2019
Bao Lige - updated : 10/09/2018
Ada Hamosh - updated : 08/21/2018
Ada Hamosh - updated : 03/05/2018
Ada Hamosh - updated : 12/20/2016
Ada Hamosh - updated : 09/12/2016
Paul J. Converse - updated : 12/23/2015
Ada Hamosh - updated : 11/23/2015
Ada Hamosh - updated : 10/13/2015
Ada Hamosh - updated : 10/2/2014
Patricia A. Hartz - updated : 12/19/2013
Ada Hamosh - updated : 12/5/2013
Ada Hamosh - updated : 10/3/2013
Patricia A. Hartz - updated : 9/20/2012
Ada Hamosh - updated : 5/15/2012
Paul J. Converse - updated : 2/14/2012
Ada Hamosh - updated : 1/12/2010
Ada Hamosh - updated : 4/28/2009
Ada Hamosh - updated : 2/18/2009
John A. Phillips, III - updated : 1/20/2009
Ada Hamosh - updated : 12/30/2008
Ada Hamosh - updated : 11/5/2008
Ada Hamosh - updated : 10/20/2008
Matthew B. Gross - reorganized : 9/4/2008
Matthew B. Gross - updated : 9/4/2008
Ada Hamosh - updated : 2/25/2008
Ada Hamosh - updated : 1/23/2008
Marla J. F. O'Neill - updated : 12/11/2007
Ada Hamosh - updated : 8/29/2007
Ada Hamosh - updated : 8/20/2007
Ada Hamosh - updated : 4/27/2007
Patricia A. Hartz - updated : 1/26/2007
George E. Tiller - updated : 9/22/2006
Ada Hamosh - updated : 7/21/2006
Ada Hamosh - updated : 2/3/2006
Ada Hamosh - updated : 9/8/2005
Paul J. Converse - updated : 4/19/2005
Ada Hamosh - updated : 1/27/2005
Patricia A. Hartz - updated : 10/11/2004
Marla J. F. O'Neill - updated : 5/5/2004
Patricia A. Hartz - updated : 11/26/2003
Patricia A. Hartz - updated : 5/6/2003
Stylianos E. Antonarakis - updated : 4/29/2003
Ada Hamosh - updated : 4/2/2003
Ada Hamosh - updated : 2/21/2003
Stylianos E. Antonarakis - updated : 2/4/2003
Ada Hamosh - updated : 11/19/2002
Stylianos E. Antonarakis - updated : 9/18/2002
Ada Hamosh - updated : 7/24/2002
Victor A. McKusick - updated : 6/6/2002
Stylianos E. Antonarakis - updated : 5/13/2002
Stylianos E. Antonarakis - updated : 1/30/2002
Ada Hamosh - updated : 12/18/2001
Dawn Watkins-Chow - updated : 10/4/2001
Paul J. Converse - updated : 8/7/2001
Stylianos E. Antonarakis - updated : 8/3/2001
Ada Hamosh - updated : 6/14/2000
Patti M. Sherman - updated : 8/31/1999
Ada Hamosh - updated : 1/29/1999
Victor A. McKusick - updated : 1/29/1999
Victor A. McKusick - updated : 9/2/1998
Victor A. McKusick - updated : 2/24/1998

Creation Date:

Victor A. McKusick : 6/23/1986

Edit History:

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carol : 04/15/2024
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alopez : 06/10/2019
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mgross : 8/3/2001
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alopez : 2/1/1999
alopez : 2/1/1999
alopez : 1/29/1999
terry : 1/29/1999
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alopez : 9/3/1998
terry : 9/2/1998
psherman : 4/15/1998
alopez : 2/25/1998
terry : 2/24/1998
mark : 11/10/1995
mimadm : 6/7/1995
davew : 7/28/1994
warfield : 4/14/1994
carol : 9/9/1993
carol : 6/25/1993

* 190080

MYC PROTOONCOGENE, bHLH TRANSCRIPTION FACTOR; MYC

Alternative titles; symbols

V-MYC AVIAN MYELOCYTOMATOSIS VIRAL ONCOGENE HOMOLOG
ONCOGENE MYC
AVIAN MYELOCYTOMATOSIS VIRAL ONCOGENE HOMOLOG
PROTOONCOGENE HOMOLOGOUS TO MYELOCYTOMATOSIS VIRUS

HGNC Approved Gene Symbol: MYC

Cytogenetic location: 8q24.21 Genomic coordinates (GRCh38): 8:127,735,434-127,742,951 (from NCBI)

Gene-Phenotype Relationships

Location	Phenotype	Phenotype MIM number	Inheritance	Phenotype mapping key
8q24.21	Burkitt lymphoma, somatic	113970		3

TEXT

Description

Cloning and Expression

Persson and Leder (1984) showed that the product of the MYC gene has a molecular mass of 65 kD, is located predominantly in the nucleus, and binds to DNA.

Mapping

Leder (1982) described in situ hybridization observations suggesting that the MYC gene is on chromosome 8 near 8q24, the breakpoint in Burkitt lymphoma (113970) translocations.

By fluorescence in situ hybridization in combination with R banding, Takahashi et al. (1991) refined the assignment of MYC to chromosome 8q24.12-q24.13, distal to fragile site fra(8)(q24.11).

Gene Function

Levens (2002) discussed and diagrammed the complex web of MYC-related pathways involved in growth, proliferation, and apoptosis.

Wernig et al. (2007) independently demonstrated that the transcription factors Oct4, Sox2, c-Myc, and Klf4 can induce epigenetic reprogramming of a somatic genome to an embryonic pluripotent state.

MYC Alterations in Cancer

Morse et al. (1988) found rearrangement of MYC in a breast carcinoma due to insertion of a LINE-1 element.

Biochemical Features

Cytogenetics

Translocations of MYC in Burkitt Lymphoma

Translocations of MYC in Other Cancers

Formation of Translocations

Molecular Genetics

Evolution

Sequences of the MYC oncogene have been highly conserved throughout evolution, from Drosophila to vertebrates (Shilo and Weinberg, 1981).

Animal Model

ALLELIC VARIANTS 4 Selected Examples):

.0001 BURKITT LYMPHOMA, SOMATIC

MYC, PRO57SER
SNP: rs28933407, ClinVar: RCV000013402

Bhatia et al. (1993) found homozygosity for a CCC-to-TCC transition converting proline-57 to serine in Burkitt lymphoma-20 (DIF) (113970).

.0002 BURKITT LYMPHOMA, SOMATIC

MYC, ASN86THR
SNP: rs121918683, ClinVar: RCV000013403, RCV000431563

Bhatia et al. (1993) found homozygosity for an AAC-to-ACC transition converting asparagine-86 to threonine in Burkitt lymphoma-21 (DS179) (113970).

.0003 BURKITT LYMPHOMA, SOMATIC

MYC, GLU39ASP
SNP: rs121918684, ClinVar: RCV000013404

Bhatia et al. (1993) found homozygosity for a GAG-to-GAC transversion converting glutamic acid-39 to aspartic acid in Burkitt lymphoma-25 (JLP) (113970).

.0004 BURKITT LYMPHOMA, SOMATIC

MYC, PRO59ALA
SNP: rs121918685, ClinVar: RCV000013405, RCV003159073

Bhatia et al. (1993) found homozygosity for a CCG to GCG transversion converting proline-59 to alanine in Burkitt lymphoma-30 (WMN) (113970).

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Contributors:

Bao Lige - updated : 08/19/2021
Ada Hamosh - updated : 06/10/2019
Bao Lige - updated : 10/09/2018
Ada Hamosh - updated : 08/21/2018
Ada Hamosh - updated : 03/05/2018
Ada Hamosh - updated : 12/20/2016
Ada Hamosh - updated : 09/12/2016
Paul J. Converse - updated : 12/23/2015
Ada Hamosh - updated : 11/23/2015
Ada Hamosh - updated : 10/13/2015
Ada Hamosh - updated : 10/2/2014
Patricia A. Hartz - updated : 12/19/2013
Ada Hamosh - updated : 12/5/2013
Ada Hamosh - updated : 10/3/2013
Patricia A. Hartz - updated : 9/20/2012
Ada Hamosh - updated : 5/15/2012
Paul J. Converse - updated : 2/14/2012
Ada Hamosh - updated : 1/12/2010
Ada Hamosh - updated : 4/28/2009
Ada Hamosh - updated : 2/18/2009
John A. Phillips, III - updated : 1/20/2009
Ada Hamosh - updated : 12/30/2008
Ada Hamosh - updated : 11/5/2008
Ada Hamosh - updated : 10/20/2008
Matthew B. Gross - reorganized : 9/4/2008
Matthew B. Gross - updated : 9/4/2008
Ada Hamosh - updated : 2/25/2008
Ada Hamosh - updated : 1/23/2008
Marla J. F. O'Neill - updated : 12/11/2007
Ada Hamosh - updated : 8/29/2007
Ada Hamosh - updated : 8/20/2007
Ada Hamosh - updated : 4/27/2007
Patricia A. Hartz - updated : 1/26/2007
George E. Tiller - updated : 9/22/2006
Ada Hamosh - updated : 7/21/2006
Ada Hamosh - updated : 2/3/2006
Ada Hamosh - updated : 9/8/2005
Paul J. Converse - updated : 4/19/2005
Ada Hamosh - updated : 1/27/2005
Patricia A. Hartz - updated : 10/11/2004
Marla J. F. O'Neill - updated : 5/5/2004
Patricia A. Hartz - updated : 11/26/2003
Patricia A. Hartz - updated : 5/6/2003
Stylianos E. Antonarakis - updated : 4/29/2003
Ada Hamosh - updated : 4/2/2003
Ada Hamosh - updated : 2/21/2003
Stylianos E. Antonarakis - updated : 2/4/2003
Ada Hamosh - updated : 11/19/2002
Stylianos E. Antonarakis - updated : 9/18/2002
Ada Hamosh - updated : 7/24/2002
Victor A. McKusick - updated : 6/6/2002
Stylianos E. Antonarakis - updated : 5/13/2002
Stylianos E. Antonarakis - updated : 1/30/2002
Ada Hamosh - updated : 12/18/2001
Dawn Watkins-Chow - updated : 10/4/2001
Paul J. Converse - updated : 8/7/2001
Stylianos E. Antonarakis - updated : 8/3/2001
Ada Hamosh - updated : 6/14/2000
Patti M. Sherman - updated : 8/31/1999
Ada Hamosh - updated : 1/29/1999
Victor A. McKusick - updated : 1/29/1999
Victor A. McKusick - updated : 9/2/1998
Victor A. McKusick - updated : 2/24/1998

Creation Date:

Victor A. McKusick : 6/23/1986

Edit History:

carol : 04/16/2024
carol : 04/15/2024
carol : 08/24/2023
mgross : 08/19/2021
carol : 03/18/2020
carol : 09/06/2019
alopez : 06/10/2019
alopez : 04/04/2019
carol : 02/14/2019
mgross : 10/09/2018
mgross : 10/09/2018
alopez : 08/21/2018
carol : 03/06/2018
alopez : 03/05/2018
carol : 09/11/2017
carol : 08/25/2017
alopez : 12/20/2016
alopez : 09/12/2016
carol : 08/11/2016
carol : 07/18/2016
mgross : 12/23/2015
mgross : 12/23/2015
alopez : 11/23/2015
alopez : 10/13/2015
alopez : 10/2/2014
mgross : 12/19/2013
mcolton : 12/19/2013
alopez : 12/5/2013
mgross : 10/4/2013
alopez : 10/3/2013
mgross : 10/16/2012
terry : 9/20/2012
terry : 6/7/2012
alopez : 5/15/2012
terry : 5/15/2012
mgross : 2/15/2012
terry : 2/14/2012
alopez : 1/12/2010
alopez : 5/6/2009
terry : 4/28/2009
alopez : 2/23/2009
terry : 2/18/2009
alopez : 1/20/2009
alopez : 12/31/2008
terry : 12/30/2008
alopez : 11/18/2008
terry : 11/5/2008
alopez : 10/21/2008
alopez : 10/21/2008
terry : 10/20/2008
mgross : 9/4/2008
mgross : 9/4/2008
alopez : 3/3/2008
terry : 2/25/2008
ckniffin : 2/5/2008
alopez : 2/4/2008
terry : 1/23/2008
carol : 12/11/2007
carol : 12/11/2007
alopez : 9/7/2007
terry : 8/29/2007
alopez : 8/28/2007
terry : 8/20/2007
alopez : 5/10/2007
terry : 4/27/2007
wwang : 3/2/2007
mgross : 1/26/2007
alopez : 9/22/2006
alopez : 9/22/2006
alopez : 7/26/2006
terry : 7/21/2006
alopez : 2/3/2006
alopez : 2/3/2006
alopez : 2/3/2006
alopez : 2/3/2006
terry : 2/3/2006
terry : 10/12/2005
alopez : 9/9/2005
terry : 9/8/2005
mgross : 4/19/2005
wwang : 2/7/2005
wwang : 2/1/2005
terry : 1/27/2005
alopez : 10/29/2004
alopez : 10/11/2004
alopez : 5/28/2004
carol : 5/5/2004
carol : 5/5/2004
mgross : 11/26/2003
alopez : 7/28/2003
alopez : 6/17/2003
alopez : 6/17/2003
mgross : 5/7/2003
cwells : 5/6/2003
mgross : 5/1/2003
mgross : 5/1/2003
terry : 4/29/2003
alopez : 4/3/2003
terry : 4/2/2003
tkritzer : 3/28/2003
alopez : 2/24/2003
terry : 2/21/2003
mgross : 2/4/2003
alopez : 11/19/2002
terry : 11/18/2002
mgross : 9/18/2002
cwells : 7/26/2002
terry : 7/24/2002
mgross : 6/11/2002
terry : 6/6/2002
mgross : 5/13/2002
mgross : 1/30/2002
alopez : 1/2/2002
terry : 12/18/2001
carol : 10/4/2001
mgross : 8/7/2001
mgross : 8/7/2001
mgross : 8/3/2001
alopez : 6/14/2000
mgross : 9/1/1999
psherman : 8/31/1999
alopez : 2/1/1999
alopez : 2/1/1999
alopez : 1/29/1999
terry : 1/29/1999
dkim : 12/15/1998
alopez : 9/3/1998
terry : 9/2/1998
psherman : 4/15/1998
alopez : 2/25/1998
terry : 2/24/1998
mark : 11/10/1995
mimadm : 6/7/1995
davew : 7/28/1994
warfield : 4/14/1994
carol : 9/9/1993
carol : 6/25/1993

NOTE: OMIM is intended for use primarily by physicians and other professionals concerned with genetic disorders, by genetics researchers, and by advanced students in science and medicine. While the OMIM database is open to the public, users seeking information about a personal medical or genetic condition are urged to consult with a qualified physician for diagnosis and for answers to personal questions.
OMIM^® and Online Mendelian Inheritance in Man^® are registered trademarks of the Johns Hopkins University.
Copyright^® 1966-2024 Johns Hopkins University.
Printed: April 25, 2024

▼ External Links

MYC PROTOONCOGENE, bHLH TRANSCRIPTION FACTOR; MYC

V-MYC AVIAN MYELOCYTOMATOSIS VIRAL ONCOGENE HOMOLOG ONCOGENE MYC AVIAN MYELOCYTOMATOSIS VIRAL ONCOGENE HOMOLOG PROTOONCOGENE HOMOLOGOUS TO MYELOCYTOMATOSIS VIRUS

TEXT

▼ Description

▼ Cloning and Expression

▼ Mapping

▼ Gene Function

▼ Biochemical Features

▼ Cytogenetics

▼ Molecular Genetics

▼ Evolution

▼ Animal Model

▼ ALLELIC VARIANTS ( 4 Selected Examples):

.0001 BURKITT LYMPHOMA, SOMATIC

.0002 BURKITT LYMPHOMA, SOMATIC

.0003 BURKITT LYMPHOMA, SOMATIC

.0004 BURKITT LYMPHOMA, SOMATIC

▼ See Also:

▼ REFERENCES

* 190080

MYC PROTOONCOGENE, bHLH TRANSCRIPTION FACTOR; MYC

V-MYC AVIAN MYELOCYTOMATOSIS VIRAL ONCOGENE HOMOLOG ONCOGENE MYC AVIAN MYELOCYTOMATOSIS VIRAL ONCOGENE HOMOLOG PROTOONCOGENE HOMOLOGOUS TO MYELOCYTOMATOSIS VIRUS

Gene-Phenotype Relationships

TEXT

Description

Cloning and Expression

Mapping

Gene Function

Biochemical Features

Cytogenetics

Molecular Genetics

Evolution

Animal Model

ALLELIC VARIANTS 4 Selected Examples):

.0001 BURKITT LYMPHOMA, SOMATIC

.0002 BURKITT LYMPHOMA, SOMATIC

.0003 BURKITT LYMPHOMA, SOMATIC

.0004 BURKITT LYMPHOMA, SOMATIC

See Also:

REFERENCES

▼

External Links

V-MYC AVIAN MYELOCYTOMATOSIS VIRAL ONCOGENE HOMOLOG
ONCOGENE MYC
AVIAN MYELOCYTOMATOSIS VIRAL ONCOGENE HOMOLOG
PROTOONCOGENE HOMOLOGOUS TO MYELOCYTOMATOSIS VIRUS

V-MYC AVIAN MYELOCYTOMATOSIS VIRAL ONCOGENE HOMOLOG
ONCOGENE MYC
AVIAN MYELOCYTOMATOSIS VIRAL ONCOGENE HOMOLOG
PROTOONCOGENE HOMOLOGOUS TO MYELOCYTOMATOSIS VIRUS