Chromosomal Translocations

CNBY 420 PPT 6

What is a chromosomal translocation?

When one part of a chromosome breaks and fuses with another part of a different chromosome

What are the two main types of translocations?

Reciprocal (equal swap) and non-reciprocal (Robertsonian, small chromosome may be lost)

What must occur for a translocation to happen?

Double-stranded DNA break followed by rejoining

Name pathological causes of double-stranded chromosomal breaks.

Ionizing radiation, oxidative free radicals, nucleases at fragile sites, failed topoisomerase II reactions, mechanical stress

What immune process can cause DNA breaks that may lead to translocation?

V(D)J recombination in T and B cells

What is a karyotype?

Process of pairing and ordering all chromosomes; uses Giemsa stain to reveal structural features

What are G bands?

Dark bands = heterochromatin (AT-rich, less active); Light bands = euchromatin (GC-rich, more active)

What does FISH stand for and detect?

Fluorescent In Situ Hybridization; labels DNA sequences on chromosomes, identifies translocations

What does spectral (multi-color) FISH allow?

Visualization of each chromosome in different colors, making translocations easy to detect

What are chromosomal territories?

Specific areas in the nucleus where chromosomes reside

In what type of cancers are translocations most common?

Hematological cancers (often as the oncogenic driver)

What is the Philadelphia chromosome?

A shortened chromosome 22 due to translocation with chromosome 9, found in CML

Which genes fuse in CML due to translocation?

BCR (ch. 22) and ABL (ch. 9) → BCR-ABL fusion protein

Why is BCR-ABL oncogenic?

It forms a constitutively active tyrosine kinase

What drug targets BCR-ABL in CML?

Imatinib (Gleevec)

Which leukemia involves t(15;17)?

Acute Promyelocytic Leukemia (APL)

Which fusion protein is formed in APL?

PML-RARα fusion protein

Why does PML-RARα cause leukemia?

It halts differentiation of promyelocytes

How is APL treated?

All-trans retinoic acid (ATRA) + chemotherapy; arsenic trioxide also effective

What are the two main consequences of chromosomal translocations in cancer?

(1) Creation of novel fusion proteins, (2) Increased oncogene expression due to promoter/enhancer rearrangement

Give an example of a fusion protein from an inversion.

EML4-ALK (ch. 2) → lung, breast, colon cancers

Give an example of a fusion protein from a duplication.

FGFR3-TACC3 (ch. 4) → glioblastoma, lung, others