Leukaemia And Lymphoma Flashcards
Where are B cells produced?
In the bone marrow
What happens once B cells have been produced?
Selected into the peripheral blood
Travel to secondary lymphoid organs eg lymph nodes and spleen
Recruited into germinal centres if there is an antigen present
What is in the cortex of lymph nodes?
B and T cells
What is in the medulla of lymph nodes?
Plasma cells
Macrophages
B cells
Sinuses which lymph can flow into
What are the different types of lymphocytes?
B and T cells
Natural killer cells
What happens if there is an antigen in a lymph node?
B cells are recruited to the germinal centre (follicles found in the cortex)
B cells evolve and produce high affinity antibodies to resist infections
What happens in somatic hypermutation?
When deaminase enzymes introduce point mutations onto the variable region of DNA that codes for the antibody
Introduces uracil to the DNA
Uracil then excised and swapped for a different base
How do mutations accumulate in somatic hypermutation?
Uracil base swapped in then replaced
B cells proliferate and mutations accumulate so that there are many different receptors with different affinities for the antigen
After proliferation of B cells, how are they selected and what happens to them?
The B cell with the highest affinity is selected and differentiates into plasma cells to produce antibodies
What is class switching antibodies and why does it happen on B cells?
IgM switches to IgG
The on is changes, variable region stays the same so affinity stays the same
Allows the antibody to interact with different effector molecules
Requires deaminase again
Why are lymph nodes a ‘perfect storm’ for cancer?
Have intense proliferation of B cells with many mutations being produced
What type of lymphoma is Burkitt’s?
A non-Hodgkin’s lymphoma
What forms of burkitt’s can you get and what is the geographical distribution?
Sporadic happen in the west
Epidemic more common in Africa
What is Burkitt’s lymphoma associated with?
EBV
Malaria
What is the mutation in Burkitt’s lymphoma?
The translocation of the MYC gene from chromosome 8 to 14, causing it to be expressed
Why can the MYC gene easily by translocated in Burkitt’s lymphoma?
Found close to constant regions
Enhancer elements normally drive transcription of these genes (antibody genes), can also drive MYC genes, causing it to be expressed
What does the MYC gene code for?
A transcription factor which causes proliferation of the cell
How can the translocation in Burkitt’s lymphoma be detected?
Fluorescence in situ hybridisation
What is FISH?
Labelled single-stranded DNA can interact with sufficiently similar complementary sequences to form complexes/hybrids
This allows specific sequences/genes to be detected
Who is follicular lymphoma typically seen in?
Older people
How do people with follicular lymphoma typically present?
Lymphadenopathy
Weight loss
Night sweats
How is follicular lymphoma treated?
Observation as it is very slow growing
What is seen histologically in follicular lymphoma?
Atypical neoplasticism follicles
Different sizes
What is the mutation in follicular lymphoma?
Translocation of the BCL-2 gene from 14 to 18
What is the result of the mutation in follicular lymphoma?
The BCL-2 gene comes under the influence of the enhancer, so is permanently switched on and over expressed.
What does the BCL-2 gene do?
Important in the intrinsic pathway of apoptosis
Prevents the association of BAC and BAX at high levels, stopping apoptosis
What does the mutation to BCL-2 in follicular lymphoma cause?
An expanded pool of cells in the germinal centre, within which further mutations leading to cancer can occur
Neoplastic infiltrate grows in atypical follicles and is composed of centrocytes and centroblasts
How is the pool of cells expanded in Burkitt’s lymphoma and follicular lymphoma in general?
Burkitt’s - have more cells going in than are dying
Follicular - normal amount going in but cells are resistant apoptosis
When does diffuse large B cell lymphoma normally occur?
Middle-age onwards
How is diffuse large B cell lymphoma treated?
Chemotherapy
It is high grade and aggressive
What is the mutation in diffuse large B cell lymphoma?
A translocation between 3 and 14
Causes the antibody heavy chain enhancer to drive expression of BCL-6 which prevents apoptosis of B cells
Why is diffuse large B cell lymphoma without a translocation given a worse prognosis?
Because the translocation is a target area of treatment
Characteristics of mantle cell lymphoma?
Aggressive but low grade
Mutation in mantle cell lymphoma?
Translocation between 11 and 14
Get over expression of cyclin D1
Allows progression their the cell cycle, past the first G1 checkpoint
Which lymphoma is only seen in immunosuppressed patients?
Primary effusion lymphoma
- transplant patients
- AIDS patients
Which virus causes primary effusion lymphoma?
KSHV
How does the KSHV virus lead to primary effusion lymphoma?
A combination of the virus and poorly characterises cellular genetic changes
KSHV can produce GPCRs which lead to proliferation and cancer
Which virus can cause adult T-cell leukaemia lymphoma?
HLTV-1
Where is adult T cell leukaemia lymphoma seen?
In the distribution of the HLTV-1 virus
- southern Japan
- equatorial Africa
- Malaysia
- Caribbean
- South America
- southern US
What are the different clinical forms of adult T cell leukaemia lymphoma?
Acute
Chronic
Smouldering
Lymphoma
How does HLTV-1 cause adult T cell leukaemia lymphoma?
Loss of Tax expression
Continuous expression of HBZ gene
What do myeloid cells give rise to?
Red blood cells Platelets Granulocytes which differentiate into -basophils -eosinophils -neutrophils
What is leukaemia?
Malignancy of leukocytes (not lymphocytes!)
What is the mutation in chronic myeloid leukaemia?
Translocation from chromosome 9 to 22 - Philadelphia chromosome
Moves the ABL gene next to the BCR gene
BCR-ABL fusion protein formed
Causes proliferation
What happens in chronic myeloid leukaemia?
Proliferation of pluripotent haemopoietic stem cells
Get proliferation and failed apoptosis
What is the most common haematological malignancy?
Diffuse large B cell lymphoma
How is gene expression profiling done?
RNA is extracted and complementary DNA is labelled and hybridised to a chip
The chip is scanned and different colours are quantified to produce heat maps
Different colours can show high and low expression due to varying levels of mRNA present
How is comparative genome hybridisation done?
Patient DNA is hybridised to reference DNA
If there is a change or deletion, it is harder to hybridise
What is looked at in array comparative genomic hybridisation? (Array CGH)
Screen for sub-microscopic chromosomal deletions for which the locus cannot be deduced from the patient’s phenotype
How is array CGH done?
An array of DNA probes covering the entire genome are applied to a solid matrix
Patient DNA and control DNA are labelled with different coloured fluorescent tags
The control and patient DNA are hybridised to the probe array
Where normal DNA exceeds that of the patient’s DNA, the patient has a deletion of that chromosomal region
What does array CGH show in DLBCL and why?
Loss of the long arm on chromosome 6
This is where BLIMP-1 is which is involved in B cell differentiation
Without BLIMP, the B cell stays germinal centre
This and high BCL-6 levels which is required to keep cells in the GC leads to lots of cells
What can flow cytometry be used for?
Diagnosis of B cell lymphoma
Gives information about how many cells of a particular type are present
Can see different levels of expression of different CD genes by different types of B cell lymphomas and can be used for diagnosis
How is flow cytometry done?
Cells stained with a monoclonal antibody which emits light
Cells sent in single file throng a chamber and hit with a laser
