Lecture 4 - B Cell Cancers Flashcards Preview

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Flashcards in Lecture 4 - B Cell Cancers Deck (65):
1

Six hallmarks of cancers

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

2

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

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

3

What predisposes B cells to becoming cancerous?

1) Somatic hypermutation
2) Isotype switching

4

How can chromosomal translocations be detected?
1)
2)

1) Dyeing of chromosomes
2) Mapping genome

5

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

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

6

Function of cyclins

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

7

Examples of inhibitors of cyclin-dependent kinases

p15, p18, p21

8

Functions of Myc
1)
2)
3)
4)

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

9

Broad function of Myc and cyclins

Promote cell division

10

Broad function of Bcl2 and BclX

Extend cell lifespan

11

Broad function of p53

DNA damage sensor

12

What is anoikis

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

13

Function of BH3-Only proteins

Initiate apoptosis

14

Function of Bcl2

Inhibit BH3-Only

15

Which protein inhibits BH3-ONly?

Bcl2

16

Which protein inhitiates apoptosis?

BH3-Only

17

How can apoptosis be triggered?

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

18

How can Bcl2 be involved in B cell cancer?

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

19

Function of Bcl6
1)
2)
3)

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

20

How can Bcl6 be involved in B cell cancers?

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

21

Which type of cancer is commonly caused by defective Bcl6?

Diffuse large B cell lymphoma

22

What normally causes Bcl6 expression to cease?

BCR activation
CD40 activation

23

Why is Bcl6 expressed in germinal centres?

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

24

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

Activate, select and differentiate B cells to combat disease
Eliminate damaged cells, or cells expressing low-affinity antibodies

25

How can mutations cause Bcl6 to become an oncogene?

1) Translocation of Bcl6 to a promotor which is always on
2) Mutation in promotor region of Bcl6. EG: prevent repressor binding to promotor

26

How can mutations occur in proto-oncogenes?

AID can have off target effects
Normally only targets Switch regions, V regions, but can accidentally target other regions

27

What is a lymphoma?

Cancer of lymph nodes

28

What is leukaemia?

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

29

What is myeloma?

Cancer of plasma cells

30

How does al lymphoma present?

A solid tumour of lymphoid cells

31

Two types of lymphoma

Hodgkins lymphoma
Non-Hodgkins lymphoma

32

Hodgkins lymphoma

Typified by presence of Reed-Sternberg cell

33

Non-Hodgkins lymphoma

A broad group of B and T cell lymphomas

34

Main demographic of acute lymphocytic leukaemia

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

35

Most common type of chronic lymphocytic leukaemia

B cell chronic lymphocytic leukaemia

36

What normally precedes myeloma?

Monoclonal gammopathy of undetermined significance

37

What is monoclonal gammopathy of undetermined significance?

A premalignant, asymptomatic stage that precedes myeloma.

Clonal plasma cell proliferation.

38

Rate of progression from monoclonal gammopathy of undetermined

About 1% per year

39

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

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

Common pathogenesis of B cell cancers

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

How can monoclonal antibody levels be detected in a patient?

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

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

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

Rank-L function

Bone reabsorption, osteoclast growth

44

OGP function

Bone reformation, osteoblast growth

45

Diagnostic criteria for multiple myeloma
1)
2)
3)

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

Is multiple myeloma curable?

No

47

What is bortezomib?

A boronic acid dipeptide
Used to treat multiple myeloma

48

Bortezomib method of action
1)
2)
3)

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

49

Function of the 26S proteosome

Large protease complex
Works with ubiquitin system to mark proteins for degradation

50

Problems with therapy with bortezomib

All cells use 26S proteosome.
Therefore many off-target effects

51

What are bisphosphonates used for?

Treating brittle bones caused by multiple myeloma

52

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

Bisphosphonates

53

What is Rituximab?

A monoclonal anti-CD20 antibody

54

Which cells express CD20?

All mature B cells
NOT plasma cells

55

How does Rituximab work?

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

56

Drawbacks of Rituxamib

Clears body of mature B cells
No effect on myelomas (CD20 not expressed on plasma cells)

57

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

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

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

Germinal centre: Most genes up-regulated
Activated blood B cell: Most genes down-regulated

59

Which diffuse large B cell lymphoma is more clinically serious?

Activated blood B cell

60

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

Germinal centre: Standard chemotherapy + Rituximab
Activated blood B cell: Specific enzyme inhibitors targeting hyperactive pathways (more aggressive treatment)

61

Trade name of ABT-263

Navitoclax

62

Chemical name of Navitoclax

ABT-263

63

Function of ABT-263
1)
2)

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

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

BH3-Only mimetic

65

Name of newer version of ABT-263

ABT-199