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BIOM30002 - M2M > Lecture 4 - B cells and Cancer > Flashcards

Lecture 4 - B cells and Cancer Flashcards

1
Q

What are the hallmarks of cancer?

A

Hanahan & Weinberg’s Landmark Paper

  • Proliferation in the absence of GFs
  • Avoiding growth suppressors
  • Avoid apoptosis
  • Angiogenesis
  • Immortality
  • Metastasis
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2
Q

What features of B cells are a cancer risk?

A
  • ‘Ignoring’ DNA damage
  • Avoiding apoptosis
  • Circulate around the body (metastasis)
  • Rapid proliferation
  • Long lived
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3
Q

What are the categories of malignancies of the immune system?

A
  • Lymphomas: solid mass, lymphocytes
  • Leukaemias: lymphocytes & leukocytes, in blood
  • Myeloma: plasma cells in BM
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4
Q

What is the importance of non-Hodgkins lymphoma?

A

It is one of the most common cancers in men and women in Australia

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5
Q

What are the two types of lymphomas?

What differentiates them?

A

• Hodgkins:
Presence of Reed-Sterberg cell
• Non-Hodgkins

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6
Q

List some B cell lymphomas

A
  • Burkitt lymphoma
  • Diffuse large B-cell lymphoma
  • Follicular lymphoma
  • Hodgkins lymphoma
  • non-Hodgkins lymphoma
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7
Q

Describe the growth rates of lymhomas

A

Can be either:
• Indolent
• Aggressive

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8
Q

What is the biggest risk factor for non-Hodgkins lymphoma?

A

Age:

• most people who get it are 60+

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9
Q

What is leukaemia?

A
  • Malignancy that starts in blood forming tissue

* results in many cancerous cells entering circulation

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10
Q

What are some B cell leukaemias?

Whom do they affect?

A
  1. ALL: Acute lymphocytic leukaemia
    • The very young and the elderly
    • B cell precursor malignancy
  2. CLL: Chronic lymphocytic leukaemia
    • Men 50+
    • Mature B cell malignancy
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11
Q

Which cells can become malignant in leukaemia?

A
  • B cells
  • T cells
  • Myeloid cells
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12
Q

What is myeloma?

A

Malignancy of plasma cells

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13
Q

Describe the progression of myeloma

A

MGUS: asymtpomatic pre-malignant phase in which there is clonal cell proliferation

Found in 3% of over 50’s

Progresses in less than 1% of cases per year

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14
Q

How are B cell malignancies classified?

A 
Physical observation:
 • Histology, Reed-Sternberg cell
 • Patient's condition
 • Karyotype
 • Flow cytometry
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15
Q

What is the Reed-Sternberg cell?

A

Mysterious but diagnostic cell seen in Hodgkins lymphoma

• has markers of both myeloid and lymphoid cells

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16
Q

What is an important diagnostic feature seen in multiple myeloma patients?

A

Increase concentrations and varied serum antibodies
• Clonal ‘paraproteins’
• Bruce Jones Proteins

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17
Q

What are clonal paraproteins?

Where are they found?

A

Abnormal Ig produced by excess clonal proliferation of B lymphocytes

They end up in the serum

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18
Q

What are Bence Jones Proteins?

Where are they found?

A

Free light chains

In blood and urine (because they are small enough to be filtered)

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19
Q

What are monoclonal antibodies (mAbs)?

A

These are antibodies that are all specific for a single epitope
The Abs are identical because they all come from identical B cells (i.e., they all come from the same clones)

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20
Q

What end organ damage occurs in multiple myeloma?

A
  1. Bone lesions and fractures
    • Increased RANKL → stimulation of osteoclasts
  2. Hypercalcemia
    • Increased break down of bone
  3. Renal insufficiency
    • So much protein in serum
  4. Anaemia
  5. Neutropaenia → infection
  6. Thrombocytopaenia → haemolytic tendency
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21
Q

What are current treatments for non-Hodgkins lymphoma?

A
  • Chemotherapy
  • Antibodies (Rituximab)
  • Irradiation
  • Bone marrow transplantation
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22
Q

Describe the features of Bortezemib

A 
"Addresses the nature of the cell"
 • A treatment for Multiple Myeloma
 • A dipeptide molecule
 • inhibits the proteasome
 • Proteasome vital part of plasma cell machinery, as they are producing such large amounts of Ig
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23
Q

What is a proteasome?

A

A piece of cellular machinery that receives ubiquitin-marked proteins for digestion

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24
Q

Discuss bisphosphonates

A

Treatment for MM

  • Inhibition of osteoclasts
  • Reduced bone resorption
  • Reduced growth

Addresses the symptoms of the cancer

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25
Q

Where is CD20 found?

A

On the surface of mature B cells

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26
Q

Describe the features of Rituximab

A

• Treatment for non-Hodgkins lymphoma
• A monoclonal anti-CD20 Ab
• Ab binds to the CD20 on mature B cells
• Leads to (transient) depletion of ALL B cells
(once off the drug, B cells come back slowly)

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27
Q

Where do malignant B cells congregate?

What is the effect of this?

A

The cells crowd the bone marrow
This disrupts all the other blood cells that are developing here
Effect:
• Cytopaenia Immunocompromise, frequent infection
• Anaemia, fatigue
• Thrombocytopaenia, haemorrhagic tendency

28
Q

What is Bcl-2?

Describe its normal function, and how it could cause cancer

A

Cell survival protein

Normal function:
• Binds BH3-only to prevent it from triggering apoptosis

In cancer:
• Involved in translocations up against the Ig gene loci
• Over-expression
• BH3 can never out-compete Bcl-2 t trigger apoptosis
• Accumulation of cells with DNA damage

29
Q

What is the down side of Bortezimib?

A

It does not selectively block proteasomes in plasma cells, rather affects all cells

30
Q

Describe the heterogeneous nature of DLBCL

A
  • Distinct types of the malignancy have been identified through gene expression profiling
  • These various types are due to the different combination of mutations that have lead to the disease

Two categories:
• GC type
• ABC type

31
Q

Describe ABT-263

A
  • a treatment for B cell lymphomas
  • This is a drug that binds Bcl-2 (displacing BH3-only)
  • this allows the cell to undergo apoptosis
32
Q

What is the most common B-cell leukaemia?

A

CLL: chronic lymphocytic leukaemia

33
Q

What are some diagnostic criteria for MM?

A

(Multiple myeloma)
• >10% clonal plasma cells on bone marrow biopsy
• monoclonal antibodies in urine or serum
• end organ damage

34
Q

What are some treatments of MM?

A
  • Bortezimib

* Bisphosphonates

35
Q

What is DLBCL?

A

Diffuse large B cell lymphoma

36
Q

Describe differences in gene expression in ABC (activated B cells) and GC B cells

A

ABC: most genes are switched off

GC B: most genes are switched on

37
Q

What are the two groups of DLBCL patients?

What treatment is appropriate for each respectively?

A

Low-clinical risk:
• Better survival rates
• GC type B cells
• Standard therapy + Rituximab

High clinical risk:
• Poor survival rates
• ABC type B cells
• Specific enzyme inhibitors targeting hyperactive pathways

38
Q

What is BH3-only?

Describe its role in apoptosis

A

Molecule in the cell that triggers apoptosis

Function

  1. Cell stress
  2. Activation of BH3 only
  3. Activation of Bax and Bak
  4. Cyt c loss from mitochondria
  5. Formation of apoptosome
  6. Activation of caspases
  7. Apoptosis
39
Q

Which molecule inhibits the action of BH3-only?

A

Bcl-2

40
Q

Which drug binds Bcl-2?
What is the effect of this?
Which disease is it used for?

A

ABT-263
• Prevents Bcl-2 from inactivating BH3-only, which normally brings about apoptosis
• Thus, the cancerous cell is no longer immortal

Use to treat B cell lymphomas with overactive Bcl-2 such as:
• CLL
• Follicular lymphoma

41
Q

What was the effect of ABT-199 in CLL patients?

A

Massive reduction in lymphocytes, killing all cancerous cells
Platelets unaffected to a large extent

42
Q

List the functions of myc

A
  1. Drives proliferation
    • Upregulation of cyclins
  2. Regulates cell growth
    • Enhances protein synthesis
  3. Inhibits differentiation
  4. Strong proto-oncogene
43
Q

What is Bcl-6?

Describe the processes it coordinates

A
  • Inhibits DNA damage response
  • Inhibits differentiation
  • Inhibits apoptosis
44
Q

What is the effect of myeloma cells on bone?

A

Malignant cells produce lots of RANK-L, which
• Increases osteoclast activity

Decreased OGP, which
• Decreases osteoblast activity

Increased resorption of bone, leaving it fragile

45
Q

What is Bcl-x?

A

Cell survival protein

46
Q

What is p53?

A

Detects DNA damage

47
Q

What are cyclins?

A

Cell growth and proliferation regulators

48
Q

What is the difference between oncogenes and proto-oncogenes?

A

Proto-oncogenes: normal cell function to do with growth and proliferation
Oncogene: inappropriately expressed proto-oncogene that causes the cell to proliferation uncontrollably

49
Q

What one of the most important proto-oncogenes?

Which cancers can it lead to?

A

Myc

Burkitts Lymphoma, through translocation up against heavy chain locus

50
Q

Describe the process leading to apoptosis when a cell experiences danger or damage

Which molecules can inhibit this?

A 
→ Damage
1. BH3-only activated
2. Bax and Bak activation
3. Mitochondria release Cyt. c (Bax and Bak punch holes in mito membrane)
4. Formation of apoptosome
5. Activation of cytoplasmic caspases
6. Digestion of cell
(apoptosis)

Bcl-2 can block BH3-only

51
Q

Which mutation is commonly seen in Follicular lymphoma and CLL?

A

Over-expression of Bcl-2

52
Q

Which molecule is vital for GC formation, as it inhibits apoptosis due to DNA damage in developing B cells?

A

Bcl-6

53
Q

What is the relationship between Bcl-6 and p53?

A

Bcl-6 inhibits p53’s action of bringing about apoptosis

54
Q

Which cancers commonly have Bcl-6 translocation?

A

DLBCL

55
Q

What happens to Bcl-6 after CD40 signalling?

A

Down regulated so that the following can occur:

  • Selection of high affinity Ig
  • Elimination of DNA damaged cells, or those with low affinity Ig through apoptosis
56
Q

How may Bcl-6 be turned into an oncogene?

A
  1. Translocation
    • Up against Ig gene locus
  2. Mutation of the repressor binding site in promoter
    • Repressor can not bind
  3. Mutations in ubiquitin binding site
    • Ubiquitin can not bind
    • Not targeted to proteasome
    • Can not be degraded

→ Continued expression on Bcl-6

57
Q

Give an example of a drug that ‘addresses the nature of the cell’

A

Bortezimib
• Malignant plasma cells (in MM) are producing a large amount of protein
• They rely on the proteasome to degrade miss-folded protein
• Bortezimib prevents the proteasome from properly functioning, so the plasma cells die

58
Q

Which mutation commonly causes DLBCL?

A

Bcl-6 overexpression

59
Q

Which mutation commonly causes CLL?

A

Bcl-2 overexpression

60
Q

Which mutation commonly causes follicular lymphoma?

A

Bcl-2 over expression

61
Q

Which cancer is Rituximab used for?

A

Non-Hodgkins lymphoma

62
Q

Describe the risk-reward balance in B cells

A

Risk: development of cancers
Reward: very efficient way of protecting against microbes

Despite the risks, B cell cancers are rare, so these processes were not removed in evolution – the benefit outweighs the risk

63
Q

How may chromosomal translocations be identified?

A

Classical / outdated:
• Karyotyping
• FISH
• Probe for myc

Now:
• Cancer genome sequencing

64
Q

Describe the B cell cancer genome map

A

Based on new sequencing technologies, many of the common (and not so common) translocations that can lead to B cell cancers have been identified

Important loci:
• IgH, IgK, IgL
• Bcl2, Myc, Bcl6

These loci are fused together

65
Q

Describe regulation of the cell cycle

A

Drivers:
• Cyclins
• Transiently expressed
• Phosphorylate Cdks

Brakes:
• p21, p15, p18
• Bind Cdks to inhibit their activity

Activated Cdks phosphorylate Rb

66
Q

What is the general function of Bax and Bak?

A

Pro-apoptotic

67
Q

Compare Ig content of blood in healthy individuals with those with MM

A

Normal:
• 10-15 mg/ml
• Heterogeneous

MM:
• 30 mg/ml
• Clonal

BIOM30002 - M2M (36 decks)

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