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MCB132 > LECTURE 5: Chromosomal Translocations & Activations > Flashcards

LECTURE 5: Chromosomal Translocations & Activations Flashcards

1
Q

How do you visualize chromosomes in single cells

A

karyotyping

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2
Q

Which phase of chromosomes are used for karyotyping?

A

Metaphase/pro-metaphase condensed chromosomes (sister chromatids visible)

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3
Q

Staining technique for chromosomes (to see banding patterns)

A

Giemsa staining

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4
Q

What is CML

A

Chronic Myelogenous Leukemia

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5
Q

What characterizes CML?

A

Philadelphia chromosome - t(9;22) reciprocal translocation

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6
Q

Translocation notation in CML

A

t(9;22)(q34;q11)
chr 9, long arm, region 3, band 4
chr 22, long arm, region 1, band 1

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7
Q

Where is BCR located?

A

Chromosome 22

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8
Q

Where is ABL located?

A

Chromosome 9

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9
Q

What does the t(9;22) translocation do?

A

Affects the ABL proto-oncogene and generates a fusion BCR-ABL protein

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10
Q

Full form of BCR

A

Breakpoint cluster region

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11
Q

Breakpoints in BCR

A

3 possible breakpoints

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12
Q

Breakpoints in ABL

A

1 possible breakpoint

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13
Q

Normal c-ABL protein structure

A

Autoinhibitory region - breakpoint - catalytic domain (tyrosine kinase)

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14
Q

How do the breakpoints affect cancer?

A

Depending on where the BCR-ABL fusion happens, protein is different
Results in different cancers (ALL, CML, CNL)

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15
Q

How does the fusion BCR-ABL protein cause cancer?

A

c-ABL is a proto-oncogene with a tyrosine kinase domain
1. The fusion removes the normal N-term autoinhibitory region
=> protein truncates, catalytic domain is always active
=> kinase is permanently switched on so overexpressed
2. BCR fusion induces clustering
=> BCR-ABL tend to cluster together in a cell
=> Clustering leads to increased self-activation of the BCR-ABL kinases - auto-activation (phosphorylation of one molecule by another)

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16
Q

What is gleevec?

A
  • Drug that targets the activated BCR-ABL catalytic domain causing remission of CML
  • One of the first targeted molecular therapies
  • Inhibits the overactive kinase of BCR-ABL and turns it off
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17
Q

What can chromosome translocations cause?

A
  • Activate proto-oncogenes (fusion proteins in CML BCR-ABL)
  • Affect proto-oncogene expression (MYC)
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18
Q

Burkitt’s Lymphoma & Translocation:
which chromosomes?

A

Translocation between chromosomes 8 and 14
t(8;14)
8q-, 14q+

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19
Q

Burkitt’s Lymphoma & Translocation:
normal vs cancer

A

Normal:
Chromosome 8 has myc
Chromosome 14 has Igh gene, highly active in immune cells

Burkitt’s Lymphoma & Translocation:
Chromosome 8 shortened
Myc from 8 translocates to 14

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20
Q

How does the t(8;14) translocation cause burkitt’s lymphoma?

A

IgH is a highly active gene
myc is a proto-oncogene

myc translocation to IgH locus results in increased expression of myc
IgH acts as a strong enhancer

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21
Q

How is the Burkitt’s translocation different from the CML one?

A

No structural changes to the protein coding sequence, simply the influence of an enhancer

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22
Q

What is myc

A

gene that codes for transcription factors

23
Q

myc translocations and types of cancer

A

translocation to the heavy or light chain of immunoglobulin -> burkitt’s lyphoma, multiple myeloma, diffuse large B cell lymphoma

translocation to the T cell receptor alpha or beta chain -> T cell lymphoblastic leukemia

24
Q

why does this myc translocation occur

A

VDJ recombination or class-switching recombination

25
translocation breakpoint of myc
first non-coding exon of myc first intron of myc ??? upstream from myc distant from myc IMPORTANT: myc protein has to be intact / unchanged
26
what is intron
non-coding sequence removed during splicing by pre-RNA
27
# hat what is an exon
coding sequence that remains in the final mRNA after splicing
28
review: how can myc cause cancer?
chromosomal translocation (t(8;14) also chromosomal amplification -> increased copies of myc at the genomic level -> overexpression
29
how are chromosomes amplified in (cancer) cells
aneuploidy gain loss HSR DM
30
HSR
homologously staining region of chromosome has tandem arrays of amplified DNA
31
DM
double minute chromosomes small extrachromosomal fragments without centromeres get lost during mitosis
32
How are HSR & DM detected?
Using FISH fluorescene in situ hybridization
33
How does HSR show up on FISH? How does DM show up on FISH?
HSR - large blocks of DNA, get integrated into the chromosome DM - small fragments
34
CGH
comparative genome hybridization
35
What is CGH?
probe normal DNA - red fluorophore tumor DNA - green fluorophore both are annealed to normal DNA in **METAPHASE** red -> gene deletion green -> gene amplification yellow -> nothing, gene present since both annealed
36
Why doesn't CGH work for philadelphia chromosome CML?
The net amount of DNA is the same (simply got translocated), so no red or green signal will show up on CGH
37
example of gene amplification causing cancer
MYCN commonly amplified in neuroblastomas
38
what is the kaplan-meier plot?
y-axis is cancer-free survival rate x-axis is time after detection/diagnosis
39
N-MYC
paralog gene of c-myc drives tumor growth correlated to poor survival rates in people with >10 copies of N-myc neuroblastoma shows up as HSR on FISH amplifications are large and recurrent, but also variable lengths amplicon will ALWAYS include myc
40
What is an amplicon
Amplified region (of DNA)
41
What is arrayCGH
Higher resolution mapping than CGH Instead of hybridizing the DNA to whole chromosomes, the labeled DNA is hybridizes to a DNA microarray - containing many small sports of DNA sequences
42
What are the genomic arrays in arrayCGH made up of?
BACs (bacterial artificial chromosomes) - segments of genomic DNA - 100kb representative oligonucleotides - ~50 probes
43
ArrayCGH analysis - what do peaks and depressions show?
Peak - candidate proto-oncogene Depression - tumor supressor gene
44
Amplification in small cell lung cancer
Done by DNA next-gen sequencing N-fib amplified, so is L-myc
45
What gene is amplified in breast cancer
ERBB2 amplification correlates with poor prognosis in breast cancer 30% of breast cancers show >5 copies of ERBB2, esp the more aggressive tumors
46
What is the genetic function of ERBB2?
human epidermal growth factor Also called HER2 first isolated in a rat neuroblastoma (also called neu)
47
What is observed in people with ERBB2 amplification? Example
Co-amplification and co-overexpression of other genes in the same region These genes also contribute to tumor development GRB7 gene binds to ERBB2 and helps activate pathways that promote cancer growth - GRB7 also links it to Ras
48
How is ERBB2 and the co-amplification observed?
Expression microarray for mRNA levels red indicates overexpression of gene product
49
How is ERBB2 targeted?
First antibody therapy Herceptin Humanized extracellular monoclonal antibody against ERBB2/HER Binds to ERBB2 protein and shuts it off blocks signal telling cell to grow
50
3 generalized models of chromosome amplifications
1. Onion skin model 2. Unequal crossing over 3. breakage-fusion-bridge cycles
51
onion skin model
chromosomal amplification occurs due to overreplication during cell replication normal replication - dna is duplicated once here - cellular origin of replication fires more than once -- additional replication --- more copies of the gene
52
unequal crossing over
unequal mitotic recombination between the sister chromatids tandem repeat in the same direction one gets duplicated, one gets deleted
53
breakage fusion bridge cycle
barbara mcclintock (1941, maize) loss of telomere at the ends of the chromosomes
54
consequences of telemore loss
1. dicentric chromosomes (2 centromeres) 2. anaphase bridge, sister chromatids fuse together, chromosome breakage => causes inverted duplications

MCB132 (7 decks)

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