chromosomal translocations (chap 6)

Define a chromosomal translocation

A structural chromosomal abnormality where a segment from one chromosome breaks and fuses with a segment of another, forming a new arrangement.

What are the two main types of translocations?

reciprocal & non-reciprocal 

Reciprocal translocation

Equal exchange of segments between two chromosomes

Non-reciprocal translocation

Unequal event, usually involving acrocentric chromosomes; often produces a small unstable chromosome that is lost.

What molecular event must occur for a translocation to happen?

A double-stranded DNA break followed by rejoining through repair pathways such as NHEJ or Alt-EJ.

What are potential pathological causes of double-stranded DNA breaks?

• Ionizing radiation

• oxidative free radicals

• nuclease activity at fragile sites

• failed topoisomerase II reactions

  • mechanical stress

Which DNA repair pathways may misjoin DNA and promote translocations?

• Non-homologous end joining (NHEJ): Fast but error-prone.

• Alternative end joining (Alt-EJ): Even more error-prone, relies on microhomology.

What role do chromosomal territories play in translocations?

Chromosomes occupy distinct nuclear areas. Proximity increases the likelihood that DNA breaks in different chromosomes will misjoin.

What is a karyotype and who developed its staining method?

A method of pairing/ordering chromosomes, usually at metaphase.

• developed by Gustav Giemsa.

What do G-dark bands indicate?

Heterochromatin, AT-rich, transcriptionally inactive.

What do G-light bands indicate?

Euchromatin, GC-rich, transcriptionally active.

What is FISH and what does it detect?

Fluorescent in situ hybridization, which labels specific DNA sequences on chromosomes to visualize translocations.

What does spectral FISH allow?

Multi-color visualization of every chromosome, making translocation detection easier and more precise.

In which cancers are translocations most common?

Hematological cancers, such as leukemias and lymphomas.

What is the Philadelphia chromosome?

A shortened chromosome 22 caused by reciprocal translocation with chromosome 9, producing the BCR-ABL fusion gene.

Who discovered the Philadelphia chromosome and when?

Peter Nowell & David Hungerford in 1959.

Who discovered that the Philadelphia chromosome was caused by a translocation?

Janet Rowley in 1972.

What is the molecular mechanism of BCR-ABL’s oncogenicity?

encodes constitutively active tyrosine kinase, driving continuous cell proliferation and survival.

What drug targets BCR-ABL in CML patients?

Gleevec (imatinib): a tyrosine kinase inhibitor that revolutionized cancer therapy.

What were the survival outcomes with Gleevec treatment?

Roughly 83%

• 10-year survival with many patients achieving long-term remission.

  • HAVE TO KEEP TAKING THE DRUG OR CANCER WILL COME BACK!

What translocation causes Acute Promyelocytic Leukemia (APL)?

t(15;17)(q22;q12) → PML-RARA fusion gene.

What is the effect of the PML-RARA fusion?

It halts the differentiation of promyelocytes, leading to accumulation of immature, nonfunctional myeloid cells.

How is APL treated?

All-trans Retinoic Acid (ATRA) with chemotherapy, or arsenic trioxide; these restore differentiation of promyelocytes.

What was the impact of the first ATRA trial in 1993?

75% of patients achieved remission, with no relapses reported.

What are the two main oncogenic consequences of translocations?

• Formation of novel fusion proteins.

• Mislocalization of enhancers/promoters that drive oncogene overexpression.

Explain how enhancer or promoter relocation can drive cancer.

A strong enhancer/promoter is translocated near an oncogene, causing abnormally high transcription even without mutation.

Give an example of enhancer-driven oncogenesis.

In Burkitt lymphoma, the MYC oncogene is translocated near immunoglobulin enhancers, leading to uncontrolled proliferation.

How does the MYC oncogene normally function?

MYC is a transcription factor regulating growth and division; overexpression removes normal growth control.

Give two examples of intra-chromosomal fusion events.

• EML4-ALK (chromosome 2 inversion) → lung cancer.

• FGFR3-TACC3 (chromosome 4 duplication) → glioblastoma and lung cancer.

Why are fusion proteins attractive therapeutic targets?

They are unique to cancer cells, not found in normal cells, making them highly specific targets for drugs.