Myc

**Function:** c-Myc is a nuclear transcription factor (bHLH-LZ) that heterodimerizes with Max to bind E-box DNA sequences. It upregulates genes for cell-cycle progression (cyclins, CDKs), ribosome biogenesis, and glycolysis/glutamine metabolism, and it represses CDK inhibitors (p21, p27). Under normal conditions it is tightly regulated and short-lived. Growth factor signaling (e.g., via Ras/MAPK) induces it. Deregulated, sustained overexpression promotes proliferation and can also sensitize cells to apoptosis (via p53/ARF), so cooperating mutations (e.g., p53 loss, BCL2) help tumors survive.

**Classification:** Proto-oncogene. Its encoded protein is a transcription factor, and this is the high-yield category on boards: oncogene products are growth factors (e.g., PDGF/SIS), receptors (RET, HER2/ERBB2), signal transducers (RAS, ABL), transcription factors (MYC), and cell-cycle regulators (cyclins, CDKs).

**Key clinical associations (activation mechanism in parentheses):** - **Burkitt lymphoma:** t(8;14) (c-myc on chromosome 8 moves next to the immunoglobulin heavy-chain gene on chromosome 14) in about 80% of cases. Less common variants are t(2;8) (kappa light chain) and t(8;22) (lambda light chain). The translocation causes constitutive overexpression. The endemic (African) form is associated with EBV and involves the jaw. The sporadic form involves the abdomen/ileocecal region. The immunodeficiency-associated form is seen in HIV. Histology shows a "starry sky" pattern (benign macrophages with tingible bodies against a dark background of monomorphic B cells). It is highly proliferative (Ki-67 ~100%), and tumor lysis syndrome is a risk with treatment. - **Neuroblastoma:** N-myc (MYCN) amplification, usually seen as double minutes or homogeneously staining regions, is associated with advanced disease and poor prognosis. Neuroblastoma arises from neural crest cells in the adrenal medulla or sympathetic chain. It presents with an abdominal mass in a child, and urine HVA/VMA are elevated. Histology shows Homer-Wright rosettes. Opsoclonus-myoclonus ("dancing eyes, dancing feet") can occur. - **Small cell lung cancer:** L-myc amplification. - **Other:** MYC amplification/overexpression occurs in many cancers, including double-hit/triple-hit high-grade B-cell lymphoma (MYC with BCL2 and/or BCL6 rearrangements), which has an aggressive course.

**Mechanisms of oncogene activation (pearl):** - Translocation (MYC in Burkitt lymphoma, BCR-ABL in CML, BCL2 in follicular lymphoma) - Amplification (N-myc in neuroblastoma, HER2 in breast cancer) - Point mutation (RAS)

**Related concept:** Oncogenes act in a dominant, gain-of-function fashion (only one allele needs to be altered), unlike tumor suppressors (e.g., p53, RB), which require loss of both alleles (Knudson two-hit hypothesis).

**Mnemonic:** "Burkitt = 8 and 14, Myc is on the scene" (c-myc, chromosome 8). Neuroblastoma = N-myc.