Question 1

Is MYC an oncogene?

Accepted Answer

Yes — MYC is a proto-oncogene that becomes an oncogene when overexpressed or amplified. It is a master transcription factor driving ribosome biogenesis, metabolic reprogramming, and cell cycle progression, and its dysregulation contributes to approximately 70% of human cancers in one form or another.

Question 2

What does MYC do in cancer cells?

Accepted Answer

Overexpressed MYC drives a transcriptional programme that forces cells into continuous proliferation, upregulating thousands of target genes involved in metabolism, protein synthesis, and cell cycle entry. MYC also paradoxically sensitises cells to apoptosis — explaining why MYC-driven cancers require co-mutations in anti-apoptotic genes like BCL2 to survive.

Question 3

What is MYCN amplification and where does it occur?

Accepted Answer

MYCN amplification is a strong adverse prognostic marker in neuroblastoma, present in ~25% of cases and associated with rapid progression and poor outcome. MYCN drives proliferation through the same transcriptional mechanisms as MYC. Amplification also occurs in small cell lung cancer, medulloblastoma, and retinoblastoma.

Question 4

Can MYC be targeted by drugs?

Accepted Answer

Direct MYC inhibition has been challenging due to its intrinsically disordered structure and lack of a druggable binding pocket. Indirect approaches — including BET bromodomain inhibitors (JQ1) that suppress MYC transcription, and Aurora A inhibitors that destabilise the MYC protein — are in clinical trials.

Question 5

What is MYC amplification and how does it drive cancer differently from other oncogenes?

Accepted Answer

MYC amplification produces many extra copies of the MYC gene (often as extrachromosomal DNA or tandem duplications), increasing MYC protein to levels far above normal mitogenic signalling. Unlike kinase oncogenes (EGFR, BRAF) that create a single constitutive signal, MYC hyperactivation simultaneously upregulates thousands of target genes across metabolism, ribosome biogenesis, cell cycle, and angiogenesis — essentially forcing an entire pro-tumorigenic transcriptional programme. MYC amplification is particularly prominent in small cell lung cancer (>60% of cases), neuroblastoma (MYCN, ~25%), and as a mechanism of resistance to targeted therapy (e.g., MYC amplification as acquired resistance to BRAF inhibitors in melanoma).

Question 6

Why does MYC overexpression paradoxically sensitise cells to apoptosis?

Accepted Answer

This is one of the most important concepts in MYC biology: overexpressed MYC directly induces its own check through ARF (p14ARF, encoded by CDKN2A). ARF sequesters MDM2 in the nucleolus, stabilising p53, which then activates pro-apoptotic targets (BAX, PUMA, BIM). Additionally, MYC directly transcribes BIM (BCL2L11) independently of p53. The result is that MYC-driven proliferation also primes cells for cell death — requiring co-mutations in BCL2 (as in Burkitt lymphoma's frequent BCL2 translocations) or TP53 loss to allow tumour survival. This paradox is therapeutically exploitable: BH3-mimetics (venetoclax) show enhanced activity in MYC-overexpressing tumours because cells are pre-loaded with pro-apoptotic signal.

Question 7

What are BET bromodomain inhibitors and how do they target MYC indirectly?

Accepted Answer

BET proteins (BRD2, BRD3, BRD4) bind acetylated lysines on histones at enhancer and promoter regions to facilitate transcription. MYC transcription is driven by a large super-enhancer — a cluster of active enhancer elements — that is exquisitely sensitive to BRD4 occupancy. BET bromodomain inhibitors (OTX-2002, ABBV-744, birabresib) displace BRD4 from super-enhancers, disproportionately reducing MYC transcription compared to other genes because super-enhancers are more BRD4-dependent than typical promoters. This selectivity means BET inhibitors suppress MYC in amplified tumours without requiring direct MYC binding. Clinical activity has been observed in MYC-amplified multiple myeloma and diffuse large B-cell lymphoma.

MYC Gene Function

Overview

More Oncogenes