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Molecule to Malady > Lecture 4 - B Cell Cancers > Flashcards

Lecture 4 - B Cell Cancers Flashcards

1
Q

Six hallmarks of cancers

A

1) Sustained proliferative signalling
2) Evades growth suppressors
3) Metastasis and invasion
4) Activating division immortality
5) Inducing angiogenesis
6) Resisting cell death

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2
Q 
What must cancers of B cells do?
1)
2)
3)
4)
A

1) Promote cell division
2) Extend lifespan of cell
3) Enable DNA mutation
4) Not necessary to promote metastasis, as B cells travel around the body anyway

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3
Q

What predisposes B cells to becoming cancerous?

A

1) Somatic hypermutation

2) Isotype switching

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4
Q

How can chromosomal translocations be detected?
1)
2)

A

1) Dyeing of chromosomes

2) Mapping genome

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5
Q 
Genes commonly translocated in B cell cancers
1)
2)
3)
4)
5)
6)
A

1) Myc
2) Cyclins
3) Bcl2
4) BclX
5) Bcl6
6) p53

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6
Q

Function of cyclins

A

Activate cyclin-dependent kinases (CDK), which drive the cell cycle

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7
Q

Examples of inhibitors of cyclin-dependent kinases

A

p15, p18, p21

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8
Q 
Functions of Myc
1)
2)
3)
4)
A

1) Upregulates cyclins
2) Downregulates cyclin inhibitors
3) Enhances rRNA and protein synthesis
4) Inhibits differentiation

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9
Q

Broad function of Myc and cyclins

A

Promote cell division

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10
Q

Broad function of Bcl2 and BclX

A

Extend cell lifespan

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11
Q

Broad function of p53

A

DNA damage sensor

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12
Q

What is anoikis

A

When a cell isn’t in it’s correct location

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13
Q

Function of BH3-Only proteins

A

Initiate apoptosis

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14
Q

Function of Bcl2

A

Inhibit BH3-Only

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15
Q

Which protein inhibits BH3-ONly?

A

Bcl2

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16
Q

Which protein inhitiates apoptosis?

A

BH3-Only

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17
Q

How can apoptosis be triggered?

A

1) Cell is stressed somehow.
2) Levels of BH3-Only exceed Bcl2
3) BH3-Only activates Bax
4) Cytochrome C released from mitochondria, apoptosome forms
5) Caspase recruitment

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18
Q

How can Bcl2 be involved in B cell cancer?

A

Overexpression of Bcl2 makes it harder for a cell to undergo apoptosis

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19
Q

Function of Bcl6
1)
2)
3)

A

1) Suppress DNA damage response in B cells (suppresses p53)
2) Essential for germinal centre formation, class switch recombination and somatic hypermutation
3) Suppresses B cell differentiation to allow for isotype switching

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20
Q

How can Bcl6 be involved in B cell cancers?

A

Translocation or mutation of Bcl6 can result in B cell DNA damage

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21
Q

Which type of cancer is commonly caused by defective Bcl6?

A

Diffuse large B cell lymphoma

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22
Q

What normally causes Bcl6 expression to cease?

A

BCR activation

CD40 activation

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23
Q

Why is Bcl6 expressed in germinal centres?

A

Prevent premature maturation of B cells, suppress normal response to damaged DNA to allow class switch recombination and somatic hypermutation to occur

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24
Q

Why is Bcl6 suppressed when B cells are activated by BCR/CD40 activation?

A

Activate, select and differentiate B cells to combat disease

Eliminate damaged cells, or cells expressing low-affinity antibodies

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25
Q

How can mutations cause Bcl6 to become an oncogene?

A

1) Translocation of Bcl6 to a promotor which is always on

2) Mutation in promotor region of Bcl6. EG: prevent repressor binding to promotor

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26
Q

How can mutations occur in proto-oncogenes?

A

AID can have off target effects

Normally only targets Switch regions, V regions, but can accidentally target other regions

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27
Q

What is a lymphoma?

A

Cancer of lymph nodes

28
Q

What is leukaemia?

A

Cancer that starts in blood-forming tissue (such as bone marrow) and spreads a large number of malignant cells into the blood

29
Q

What is myeloma?

A

Cancer of plasma cells

30
Q

How does al lymphoma present?

A

A solid tumour of lymphoid cells

31
Q

Two types of lymphoma

A

Hodgkins lymphoma

Non-Hodgkins lymphoma

32
Q

Hodgkins lymphoma

A

Typified by presence of Reed-Sternberg cell

33
Q

Non-Hodgkins lymphoma

A

A broad group of B and T cell lymphomas

34
Q

Main demographic of acute lymphocytic leukaemia

A

Peak incidence at 2-5 years, and another peak in old age

35
Q

Most common type of chronic lymphocytic leukaemia

A

B cell chronic lymphocytic leukaemia

36
Q

What normally precedes myeloma?

A

Monoclonal gammopathy of undetermined significance

37
Q

What is monoclonal gammopathy of undetermined significance?

A

A premalignant, asymptomatic stage that precedes myeloma.

Clonal plasma cell proliferation.

38
Q

Rate of progression from monoclonal gammopathy of undetermined

A

About 1% per year

39
Q 
Classification of B cell malignancies is based on:
1)
2)
3)
4)
5)
6)
A

1) Patient presentation
2) Histology of tumour or involved blood
3) Karyotype of tumour cells
4) Abnormal accumulation of clones of cells
5) Flow cytometry of B cells using monoclonal antibodies, that recognises surface molecules (CDs) on malignant cells
6) Abnormal number of monoclonal antibodies detected in blood

40
Q

Common pathogenesis of B cell cancers

A

1) Malignant B cells crowd out other cells in bone marrow
2) Severely limits function of normal haematopoietic cells
3) Symptoms can include infection, bleeding problems, respiratory failure

41
Q

How can monoclonal antibody levels be detected in a patient?

A

1) Run patient serum on a gel
2) Normally, antibodies are different, and will therefore not produce a strong band on a gel
3) If there are a large number of monoclonal antibodies, a strong band will appear

42
Q 
How can myelmoa lead to brittle bones?
1)
2)
3)
4)
A

1) Myeloma cells bind to stromal cells in bone marrow
2) Overexpression of Rank-L
3) Underexpression of OGP
4) Results in osteoclastogenesis and osteolysis

43
Q

Rank-L function

A

Bone reabsorption, osteoclast growth

44
Q

OGP function

A

Bone reformation, osteoblast growth

45
Q

Diagnostic criteria for multiple myeloma
1)
2)
3)

A

1) Over 10% bone marrow plasma cells in bone marrow
2) Monoclonal antibodies in serum or urine (Bence Jones proteins in urine)
3) End organ damage: Bone lesions and fractures, hypercalcaemia, renal insufficiency, anaemia, frequent severe infection

46
Q

Is multiple myeloma curable?

A

No

47
Q

What is bortezomib?

A

A boronic acid dipeptide

Used to treat multiple myeloma

48
Q

Bortezomib method of action
1)
2)
3)

A

1) Inhibits function of 26S proteosome
2) B cell can’t degrade proteins, including NF-KB
3) B cell undergoes apoptosis

49
Q

Function of the 26S proteosome

A

Large protease complex

Works with ubiquitin system to mark proteins for degradation

50
Q

Problems with therapy with bortezomib

A

All cells use 26S proteosome.

Therefore many off-target effects

51
Q

What are bisphosphonates used for?

A

Treating brittle bones caused by multiple myeloma

52
Q

What is a treatment for brittle bones caused by multiple myeloma?

A

Bisphosphonates

53
Q

What is Rituximab?

A

A monoclonal anti-CD20 antibody

54
Q

Which cells express CD20?

A

All mature B cells

NOT plasma cells

55
Q

How does Rituximab work?

A

Binds mature B cells, marks them for destruction by the immune system

56
Q

Drawbacks of Rituxamib

A

Clears body of mature B cells

No effect on myelomas (CD20 not expressed on plasma cells)

57
Q

Way to differentiate between two types of diffuse large B cell lymphoma

A

Using a microarray
Oligonucleotides on microarray for every gene in the human genome
Can be used to see which genes are most highly expressed in a cell type

58
Q

Different microarray expression patterns for germinal centre B cells and activated blood B cells

A

Germinal centre: Most genes up-regulated

Activated blood B cell: Most genes down-regulated

59
Q

Which diffuse large B cell lymphoma is more clinically serious?

A

Activated blood B cell

60
Q

Difference in treatments for germinal centre DLBCL and activated blood B cell DLBCL

A

Germinal centre: Standard chemotherapy + Rituximab

Activated blood B cell: Specific enzyme inhibitors targeting hyperactive pathways (more aggressive treatment)

61
Q

Trade name of ABT-263

A

Navitoclax

62
Q

Chemical name of Navitoclax

A

ABT-263

63
Q

Function of ABT-263
1)
2)

A

1) Mimics shape of BH3-Only, binds preferentially to Bcl2 BH3-Only binding site
2) Displaces BH3-Only from Bcl2 binding-site, allowing BH3-Only to initiate apoptosis in cell

64
Q

What type of drugs are ABT-263 and ABT-199?

A

BH3-Only mimetic

65
Q

Name of newer version of ABT-263

A

ABT-199

Molecule to Malady (35 decks)

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