MYCN

Question 1

What is the role of MYCN in normal cells?

Answer 1

• ESC pluripotency and renewal
• rise and fall during development
• homozygous deletion of MYCN in mouse embyos is lethal

Question 2

Where are MYCN abberations seen?

Answer 2

in neuroblastoma
- also in leukaemia, retinoblastoma and more

Question 3

How is MYCN regulated at the protein level?

Answer 3

• as cells go through the cell cycle MYCN is turned up and then degraded
• ser62 is phosphorylated by cycins to stabilise MYCN
• tyr58 is then phosphoryalated and MYCN is activated
• removal of ser62 phosphorylation causes MYCN to attract ubiquitin ligase and get degraded

Question 4

Name some genes regulated by MYCN

Answer 4

• ALK upregulated
• TERT upregulated
• NGFR donwnregulated

Question 5

MYCN can cause gene expression and repression by forming respective complexes. What are they?

Answer 5

Activation: forms a dimer with Max to bind DNA E-box and interacts with proteins such as acetyltransferases
Inactivation: binds inhibitor elements on the DNA with the MIZ-1 cofactor and brings in EZH2, histone deacetylases and DNMT3A

Question 6

What is the role of ALK?

Answer 6

oncoprotein involved in the promotion of proliferation, migration and invasion

Question 7

What is the role of TERT?

Answer 7

telomerase reverse transcriptase maintains telomeres

Question 8

What is the role of NGFR?

Answer 8

neurotrophin receptor that promotes neuronal differentiation and represses growth

Question 9

What occurs when both MYCN overexpression and ALK mutations are present in neuroblastoma?

Answer 9

• MYCN upregulates mutated ALK
• worse prognosis
• ALK = best
• MYCN = medium
• both = worst
• ultra high-risk neuroblastoma

Question 10

How does ALK stabilise MYCN at the protein level?

Answer 10

allows it to accumulate in the cell by phosphorylating it + preventing its ubiquitination and degradation

Question 11

Give an example of how MYCN regulates miRNAs

Answer 11

• MYCN upregulates miR-17-92
• these target nueclear receptors and decrease their expression
• leads to decreased levels of differentiation and development in the sympathetic NS -> neuroblastoma
• also LIM28B (let-7)

Question 12

What are Lim28B and Let-7?

Answer 12

• miRNAs
• let-7 acts as a TSG that represses ras, myc etc
• LIM28B can repress let-7 processing and act as an oncogene
• LIM28B is upregulated by MYCN and increased expression can lead to neuroblastoma and wilm’s tumour
• also seen as a result of chromosome losses reducing let-7

Question 13

What is synthetic lethality?

Answer 13

Specific cell death resulting from the simultaneous mutation of two non-lethal genes, which individually allow cell survival - causes death of cancer cells - target pathways cancer cells are overly reliant on where normal cells arent

Question 14

What are some pathways/elements that can be targeted in MYCN neuroblastoma?

Answer 14

• CDK2
• aurora kinase A
• PRMTs

Question 15

How can CDK2 be targetted in neuroblastoma?

Answer 15

• CDK2 inhibitors used in MYCN-amplified neuroblastoma cells kills the cells
• some MYCN neuroblastomas must be reliant on CDK2 pathways such as using Rb inactivation to drive cell cycle progression
• small molecule inhibitors can be used to do this - roscovitine

Question 16

What is the role of aurora kinase A in neuroblastoma?

Answer 16

• stabilises MYCN by blocking its ubiquitination and degradation
• high levels of AKA causes a lack of terminal differentiation that creates a larger pool of cells to become neuroblastoma
• allosteric inhibitors can block aurora kinase A from doing this

Question 17

What are PRMTs?

Answer 17

• inhibitors of arginine methyltransferases
• prevent apoptosis in cancer cells
• can become reliant on these pathways
• can use inhibitors such as SAH to prevent this