Lecture 4 - B Cell Cancers Flashcards
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
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
What predisposes B cells to becoming cancerous?
1) Somatic hypermutation
2) Isotype switching
How can chromosomal translocations be detected?
1)
2)
1) Dyeing of chromosomes
2) Mapping genome
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
Function of cyclins
Activate cyclin-dependent kinases (CDK), which drive the cell cycle
Examples of inhibitors of cyclin-dependent kinases
p15, p18, p21
Functions of Myc 1) 2) 3) 4)
1) Upregulates cyclins
2) Downregulates cyclin inhibitors
3) Enhances rRNA and protein synthesis
4) Inhibits differentiation
Broad function of Myc and cyclins
Promote cell division
Broad function of Bcl2 and BclX
Extend cell lifespan
Broad function of p53
DNA damage sensor
What is anoikis
When a cell isn’t in it’s correct location
Function of BH3-Only proteins
Initiate apoptosis
Function of Bcl2
Inhibit BH3-Only
Which protein inhibits BH3-ONly?
Bcl2
Which protein inhitiates apoptosis?
BH3-Only
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
How can Bcl2 be involved in B cell cancer?
Overexpression of Bcl2 makes it harder for a cell to undergo apoptosis
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
How can Bcl6 be involved in B cell cancers?
Translocation or mutation of Bcl6 can result in B cell DNA damage
Which type of cancer is commonly caused by defective Bcl6?
Diffuse large B cell lymphoma
What normally causes Bcl6 expression to cease?
BCR activation
CD40 activation
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
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
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
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
What is a lymphoma?
Cancer of lymph nodes
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
What is myeloma?
Cancer of plasma cells
How does al lymphoma present?
A solid tumour of lymphoid cells
Two types of lymphoma
Hodgkins lymphoma
Non-Hodgkins lymphoma
Hodgkins lymphoma
Typified by presence of Reed-Sternberg cell
Non-Hodgkins lymphoma
A broad group of B and T cell lymphomas
Main demographic of acute lymphocytic leukaemia
Peak incidence at 2-5 years, and another peak in old age
Most common type of chronic lymphocytic leukaemia
B cell chronic lymphocytic leukaemia
What normally precedes myeloma?
Monoclonal gammopathy of undetermined significance
What is monoclonal gammopathy of undetermined significance?
A premalignant, asymptomatic stage that precedes myeloma.
Clonal plasma cell proliferation.
Rate of progression from monoclonal gammopathy of undetermined
About 1% per year
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
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
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
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
Rank-L function
Bone reabsorption, osteoclast growth
OGP function
Bone reformation, osteoblast growth
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
Is multiple myeloma curable?
No
What is bortezomib?
A boronic acid dipeptide
Used to treat multiple myeloma
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
Function of the 26S proteosome
Large protease complex
Works with ubiquitin system to mark proteins for degradation
Problems with therapy with bortezomib
All cells use 26S proteosome.
Therefore many off-target effects
What are bisphosphonates used for?
Treating brittle bones caused by multiple myeloma
What is a treatment for brittle bones caused by multiple myeloma?
Bisphosphonates
What is Rituximab?
A monoclonal anti-CD20 antibody
Which cells express CD20?
All mature B cells
NOT plasma cells
How does Rituximab work?
Binds mature B cells, marks them for destruction by the immune system
Drawbacks of Rituxamib
Clears body of mature B cells
No effect on myelomas (CD20 not expressed on plasma cells)
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
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
Which diffuse large B cell lymphoma is more clinically serious?
Activated blood B cell
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)
Trade name of ABT-263
Navitoclax
Chemical name of Navitoclax
ABT-263
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
What type of drugs are ABT-263 and ABT-199?
BH3-Only mimetic
Name of newer version of ABT-263
ABT-199
