Session 4 - Molecular Biology of Leukaemia and Lymphoma Flashcards
Outline the process of normal B cell development
- Antibody producing cells
- Formed in the bone marrow
- Transported to peripheral tissue for further maturation in the lymph nodes => process occurs as first antibodies are beginning to be expressed
- Undergoes proliferation in the germinal centres of the lymph nodes
What process happens to B cell in the lymph nodes
• Somatic hyper-mutation
What is somatic hyper-mutation, what are its benefits and what can it lead to?
o Cysteine in the region of the genome coding for the variable chain of antibodies is deaminated via specific enzymes
o Cytosine deamination leads to double stranded break in the DNA and rearrangement
o The repair process causes mutation
o This give diversity to antibodies
o Occurs in the cells that are most highly proliferating cells in the human body
o DNA breaks and proliferation => ideal way to produce lymphomas
What does epstein barr virus do?
• Attaches and activates B-lymphocytes CD21
- Enters cell and undergoes lytic replication
What is EBV associated with? Three conditions
o Heterophile positive infectious mononucleolus
o Burkett’s Lymphoma
o Nasopharyngeal Carcinoma
Give two types of burkitt’s lymphoma
o Sporadic (west) o epidemic (viral Epstein-Barr)
What is the histology of burkitt’s lymphoma cells?
o Sheets of cells => tangible body macrophages
o Starry sky appearance
o Blue with large nuclei
What is the reciprocal chromosomal translocation in Burkitt’s lymphoma?
t(8,14) - Moves c-myc to an area of 14 regulated by antibody heavy chain locus.
This cuases uncontrolled constitutive expression of the gene.
What does c-myc do in a cell?
- Master regulator of cell metabolism and proliferation
- If overexpressed leads to many metabolic changes in the transformed cells
- Function in cell cycle and proliferation
- Allows cell transformation in translocation
How can chromosomal 8:14 translocation be diagnosed?
o Fluorescent in situ hybridisation
Look for large translocation
What proportion of non-hodgkin’s lymphoma does follicular lymphoma make up?
20-30%
Give some signs and symptoms of follicular lymphoma
o enlargement of the lymph nodes in the neck, underarm, stomach, or groin, o fatigue, o shortness of breath, o night sweats, o weight loss
What is the gene change in follicular lymphoma?
• Reciprocal translocation between 14 and 18, t(14,18)
o Affects BCL2
What is the function of BCL2 in the cell?
o Involved in cell survival
o Prevents apoptosis via intrinsic pathway
Prevent oligomerasation of BAX and BAK
• When oligomerised they creates a hole in the mitochondria allowing initiation of apoptosis
Stabilises mitochondria to resist apoptotic stimuli
o Cell immortalisation
What is the mechanism of action of BCL2 upregfulation in carcinogenesis
o Reduced apoptosis => allows further mutations and progression to cancerous state
What is the chromosomal translocation in diffuse large B-cell lymphoma?
• Chromosomal translocation t(3,14) • BCL6 is affected o If found at very high levels Protective outcome Better response to conventional chemotherapy
What does increased bcl-6 do?
o Maintains the germinal cell proliferations
o If downregulated B cells exit the germinal cells but when it is upregulated they remain in the germinal centres increasing level of proliferation and leading to further mutations
o The disease is very heterogenous
Give some gene markers for
Diffuse large B-cell lymphoma? o CD10 o BCL6 o MUM1 o Potential way to distinguish between different co-types o Not entirely successful
How can genetic changes be tested in diffuse large B-cell lymphoma
o Tested by DNA hybridisation in diffused large B-cel lymphoma
Give some others changes in diffuse large B-cell lymphoma
o Lost
o BLIMP1 is lost
Stimulates differentiation of B cells once they leave the germinal centre
Downregulates BCL6 in order to allow exiting of the cells out of germinal centres
Lack of it will induce greater proliferation
What does BCL6t enhancement and BLIMP loss lead to?
• BCL6 enhancement and BLIMP loss leads to increased time period of proliferation of B cells leading to induction of mutations and cancer development
What happens genetically in mantle cell lymphoma?
Translocation t(11,14) Heavy chain and cyclin D1 Cyclin D1 o Comes on in G1 and drives cells into synthesis phase o Maintains proliferation Many varieties
What can be used to detect diffeent types of mantle cell lymphoma
Flow cytometry can be used to detect different types of Mantle cell lymphoma
o Detects surface markers
o Mechanical means => single cell hit by laser
1. Monoclonal antibodies bind to the certain receptors
2. Antibodies are fluorescently labelled
3. Type of antibody can be detected as it is hit by the laser emitting light signal
What viruses are found lymphoma?
HHV8
HTLV-1
What does HHV8 cause lymphoma wise?
o Primary effusion lymphoma
o Only in immunosuppressed patients (transplants and HIV)
o 3 different diseases
o Virus protein can insert into the cell and activate GPCR stimulating proliferation
What does HTLV-1 cause lymphoma wise/
• Adult T-cell leukaemia lymphoma
What does adult T-cell leukaemia cause?
o Affects CD4 and CD25
Positive cells
o Clinical forms
What occurs in acute adult t-cell lymphoma
Acute leukaemia
• Leukaemic picture, organomegaly, high lactate dehydrogenase (LDH) and often hypercalcaemia
What occurs in chronic adult t-cell leukaemia?
- Lymphocytosis >4×109/l with ATLL cells, skin, lung, liver or node
- involvement
- Calcium levels normal, LDH normal or less than twice the upper normal limit
What is chemoprevention?
Use of natural or synthetic compounds to reverse, suppress, prevent or delay carcinogenic progression to invasive cancer
Give some lifestyle suggestions for protecting yourself from Cancer
1) Be as lean as possible without being underweight
2) 30 minutes physically active 30 mins/day
3) Avoid sugary drinks – Limit consumption of energy dense foods
4) Eat more varieties of vegetables, fruits, whole-grains and pulses
5) Limit consumption of red meats and avoid processed meats
Give two types of Chemopreventive Agents in Cancer
Blocking agents
Supressing agents
What are blocking agents?
Compounds which inhibit carcinogenesis by preventing carcinogens from being generated or from reaching, or reacting with, critical target sites in tissues.
What are supressing agents?
Compounds which act after carcinogenic exposure by suppressing the expression of neoplasia
What is the difficulty when you’re assessing the efficacy of Chemoprevention?
There has to be a palpable end to the trial – requires the use of surrogate end point biomarkers
What two issues does the use of surrogate end point biomarkers bring up
requires a detailed understanding of the Cancer process in any given tissue and a detailed understanding of the mechanism of action of the chemopreventive agent.
What are some host factors which differ from patient to patient?
Drug metabolising enzymes – Susceptibility to carcinogenic effects of cigarette smoke – altered response to chemopreventive agents which require metabolism
Repair enzymes – Ability to repair DNA
Receptors, kinases, transcription factors – Cell signalling
Why is a diet targeted therapy good?
Need agents where there is pre-existing evidence of safety. Often consumed in diet regularly, considered relatively safe. Multi-targeted – can interfere with many pathways involved in carcinogenesis.
Give two models of carcinogenesis?
Chemical models
Mutant or genetically engineered models
What are chemical models of carcinogenesis?
Tumours in rodents induced by chemical carcinogens. Tumour development rapid; localisation and nature of tumour dependent on dose, strain of rodent etc
What are some mutant or genetically engineered models?
Rodents which carry mutations in genes implicated in the initiation or progression of cancer or where the gene can be knocked out or mutated.
Give three examples of agents which were attempted chemoprevenativie agents
Tamoxifen
Aspirin
B-carotene
Why was tamoxifen used, and what’s wrong with it?
Anitoestrogen in breast tissue, benefits extended beyond 5-years of treatment. Endometrial cancer and venothrombolic events increased, however – Devil and the deep blue sea!
Why was aspirin used?
Low dose aspirin reduces inlammation and thus cancer promotion
What happened with beta carotene?
Believed it would be a useful chemopreventive agent for lung cancer, actually proved the opposite. May have been wrong dose, perhaps converted to co-carcinogen in presence of tobacco smoke. Other consitutents of the fruits and vegetables ingested to eat B-carotene may have been the cause.
