Lecture 10 - Diseases of the Blood Flashcards
Why do we feel ill during inflammation / infection?
Cytokines released by neutrophils
Describe the structure of the hematopoietic stem cell niche
• Stem cells, but also:
- Endothelial cells
- Osteoblasts
- Innervation & vasculature
- Stromal cells
What is the name for a decrease in the n° of white blood cells?
What about increase in n°?
Leukopenia: decrease
Leukocytosis: increase
What are some specific subtypes of leukopenia?
Neutropenia:
• Reduction in neutrophils
• Due to a wide variety of inflammatory reactions
• Not usually clinically significant
Agranulocytosis:
• Clinically significant reduction in neutrophils
• Susceptibility to bacterial and fungal infections
Outline the various causes of neutopaenia
- Decreased production
• Stem cell suppression
• Drugs (Chemotherapy, antibiotics)
• Inherited defects: Kostmann syndrome - Increased destruction
• Immune mediated (SLE)
• Splenomegaly, splenic sequestration
• Increased peripheral demand
What are aplastic anaemias?
Low RBC numbers
What is splenic sequestration?
What can it lead to?
Spleen blockage (secondary to another disease; e.g. sickled cell anaemia) The spleen will have increased functionality, and thus lead to increased destruction of neutrophils (neutropaenia)
Describe immune mediated increased destruction of neutrophils
Cause:
• Idiopathic
• Due to a disorder (e.g. SLE)
List factors leading to leukocytosis
- Size of the myeloid and lymphoid progenitor pools in BM
- Rate of release from storage pools
- Size of marginal pool
- Rate of extravasation
What pathological features are seen in neutrophils in leukocytosis
- Toxic granulations
- Döhle bodies (cytoplasmic inclusions)
- Cytoplasmic vacuoles
What is Lymphadenitis?
Describe some of the features & cause
Very sore lymph nodes
Cause:
• Microbial drainage from teeth and tonsils
• Systemic viral infection
• Bacteraemia
Features
• Usually self limiting
• Often experienced at the beginning of a cold
• Much lymphocyte hyperplasia of the lymph nodes
What are the categories of neoplasms of white blood cells?
Lymphoid
• Involving lymphocytes
Myeloid
• Involving innate immune cells
Leukaemia:
• Bone marrow involvement
• Large numbers of neoplastic cells entering blood
Lymphomas:
• Solid mass tumours
List some myeloid neoplasms
- Acute myeloid leukaemia (AML)
- Myelodysplastic syndromes
- Chronic myeloid leukaemia (CML)
Describe the Philadelphia chromosome
Which neoplasms can it bring about?
- T(9;22) chromosomal translocation
- Bcr-Abl fusion protein; constitutively active tyrosine kinase
- ‘Always on’ → proliferation
Can lead to acute leukaemias
Why are white blood cells in particular susceptible to translocations?
Due to the high levels of proliferation
→ Sheer number, statistically, there will be errors
What is leukaemia?
Malignancy of progenitor cells in the bone marrow
What is the molecular pathogenesis of leukaemias?
What is the result of these mutations?
Give some examples
- Chromosome translocations
- Transcription factor mutations
Result:
• Increased proliferation
• Increased self-renewal
• Decreased differentiation
e. g.
1. t(9;22) → Philadelphia chromosome
2. MLL protein fusion / rearrangement
What is the aetiology of acute leukaemia?
- Genetic factors
- Chronic immune stimulation
- Iatrogenic factors
- Smoking
- Infectious causes
Describe genetic factors leading to acute leukaemia
Non random chromosomal abnormalities:
• Chromosomal translocations (bcd-abl)
• Transcription factor mutations:
- Duplication of MLL protein
- Fusion of MLL with a ‘fusion partner gene’
What are some iatrogenic factors of leukaemia aetiology?
- Irradiation
* Chemotherapy
Describe how infectious agents can bring about leukocyte neoplasms.
List the infectious agents
- HPV
- EBV
- Human T-cell leukaemia virus (HTLV)
- Kaposi sarcoma herpesvirus (KSHV)
Describe chronic immune stimulation causing acute leukaemia
- H. pylori infection → gastric B-cell lymphoma
* Gluten sensitive enteropathy → intestinal T-cell lymphoma
Which cells are affected in the vast majority of lymphoid neoplasms?
B cells (90%)
The rest are of course T cell based
Describe the onset of acute leukaemias
Very abrupt
Onset is seen within days or weeks of the first symptoms
What are the symptoms of ALL?
Related to depression of bone marrow function
- Anaemia → fatigue
- Neutropaenia → infection → fever
- Thrombocytopaenia → haemorrhagic tendency
Neoplastic cell expansion →
• Bone pain
• Headache
• Nausea
Compare prognosis of ALL in adults and children
Children: 95% remission, 80% cure
Adults: 40% remission
Describe the mutations needed to cause ALL
Chromosomal mutations
• Dysregulation of transcription factor production
→ Aberrant signalling in B and T cell development
NB single mutations aren’t sufficient to cause cancer
→ Build up of mutations required
Compare common mutations in B and T cell ALL
T cell:
• NOTCH1 TF
B cell:
• PAX5 TF
• E2A TF
What are the pathological differences between AML and ALL?
Different surface markers of the neoplastic cells
AML:
• More cytoplasm seen in blasts than ALL
What are the risk factors for MM?
- Men
* Elderly
What is seen in the skull on an X ray in MM?
Black dots, indicating decreased calcification
What histological features are seen in plasma cells in MM?
- Many vacuole type structures containing much Ig
* Spots visible within the nuclei
Describe biochemical diagnosis of MM
‘Blood Ab electrophoresis tests’
- Normal:
• Smear of IgG: indicates diverse range of Ig, as in normal immune response - MM patient serum:
• Single band: indicates a single specificity of IgG
Which pathway is affected in MM?
What is the role of this pathway?
The hedgehog pathway
• Important for stem cell self-renewal
• In MM; the pathway is overactive (active w/o stimulus)
• Cells constantly self renew and proliferate
Describe the action of myeloma cells bringing about the main pathologic feature of MM
- Myeloma cells produce MIP1a
- MIP1-α increases RANKL expression from BM stromal cells
- RANKL activates osteoclasts
- Bone resorption
What is smouldering MM?
Asymptomatic, pre-clinical stage very common in older people (3%)
What are the treatments of MM?
Chemotherapy (quite effective)
Different treatments based on ‘type’
What controls the development of the various WBCs from stem cells in the bone marrow?
Cytokines
What’s the name for a clinically significant reduction in neutrophils and increased susceptibility to bacterial and fungal infections?
Agranulocytosis
Which drugs can cause Leukopenia?
Chemotherapy
Many antibiotics
What is the name for sore lymph nodes?
Lymphadenitis
What is seen in histological sections of the lymph node in lymphadenitis?
- Increased n° of GC’s in lymph nodes
* Increased cell density in GC’s and nodes in general
Compare AML and CML
AML:
• Accumulation of immature progenitors in BM
• Acute onset
CML:
• Increased production of one (or more) terminally differentiated WBC’s
Which mutation is commonly seen in ALL?
Philadelphia chromosome due to chromosome translocation
Describe what happens to cells in ALL
Greatly increased numbers of blasts (immature B or T cells)
How is ALL diagnosed?
- Blood smear
• Presence of great numbers of blasts - Expression of B cell markers, indicating increased n°’s of blasts
Why is MM a significant disease?
1% of all cancer deaths in western countries
What is the main risk factor for MM?
Old age
Which organ is most affected by MM?
Bone
Which isotope of monoclonal Ab is most commonly seen in MM?
Which classes are uncommon?
IgG is common (also IgA)
IgM, IgE & IgD are uncommon
Which factors promote the proliferation and survival of MM cells?
Autocrine and paracrine signals from stromal cells:
• IL-6
Describe the variability in severity of MM
Good outcome: associated with translocations involving cyclin D
Poor outcome: certain deletions
Is chemotherapy effective in MM?
What about for Anaplastic Large-Cell lymphoma?
MM: Yes
→ 50-70% remission
ALCL:
→ up to 80% cure rate
What is Anaplastic large cell lymphoma?
• ALK positive: anaplastic lymphoma kinase gene rearrangement
→ Constitutively active tyrosine kinases
→ Proliferation and cell survival
Why ALK positive?
Anaplastic lymphoma kinase is present
Why is ALK positive a great opportunity for a vaccine?
Inhibitors of ALK (the overactive tyrosine-kinase) are in development
This is a chance for a great selective, targeted therapy
Also, ALK-antigen is a target for vaccine development
