Haematopoietic System Malignancies 2

Lymphomas
1. Malignancy of lymph nodes
2. Hodgkins Lymphoma
3. Non-Hodgkin's Lymphoma
  1. Diffuse large B cell lymphoma
  2. Follicular lymphoma
  3. Lots of others
Hodgkin's Disease
1. Often seen in young adults
2. Epstein-Barr virus is often integrated in malignant cells
3. Reed-Sternberg cells are malignant cells - surrounded by a sea of normal immune cells
4. Curable with chemotherapy/radiotherapy in most cases
Non-Hodgkin's Lymphoma
1. Mantle cell lymphoma
2. Small lymphocytic lymphoma
3. Follicular lymphoma
  2. Indolent (slow growing) but curable
  3. 10 year median survival
  4. Patients present with lymphadenopathy
  5. t(14;18) present in 90% of cases
    1. Increases expression of BCL2 (anti-apoptosis protein)
      1. Translocation puts BCL2 near immnoglobulin heavy chain gene
    2. BCL2 inhibitors in clinical trials
4. Diffuse large B cell lymphoma
  1. Most common
  2. Lymph node replaced by large sheets of lymphoma cells
    1. Large cells in diffuse sheets
  3. Potentially curable
    1. Monoclonal antibody therapy
      1. Cells express CD20
      2. Rituximab (antibody against CD20) kills lymphoma cells
        Signal for apoptosis via complement cascade and MAC
        Cells engulfed by macrophages
  4. Aggressive
Epigenetic Regulation of Gene Expression
1. EZH2 methylates K27, inhibiting transcription
  1. Gain of function in 27% follicular lymphoma
  2. Both mutations reduce transcription
2. MLL2 methylates K4, increasing transcription
  1. Loss of function of MLL2 in 90% follicular lymphomas
Chronic Lymphocytic Leukaemia (CLL)
1. Lymphoma of the blood/bone marrow
2. Caused by chronic proliferation of mature B cells
3. Usually presents with abnormal blood tests (discovered in routine test)
  1. Very high white blood cells count - 200 (normal is 10)
4. Can present with lymphadenopathy
5. B cell activation
  1. Antigen binds
    1. Lyn kinase phosphorylates Syk kinase
      1. Activates Bruton tyrosine kinase
        Phosphorylates Plcg
        Activates DAG and IP3
        Increases Ca2+
        Proliferation and survival via Nf-kappaB
  2. Lyn kinase, Syk kinase and Bruton tyrosine kinase all increased in CLL
    1. Bruton tyrosine kinase inhibitors are in late stage clinical trials - have efficacy
Myeloma
1. Common
2. Plasma cells have become malignant
3. Produce an antibody which forms a monoclonal band in serum electrophoresis
  1. Not present in normal patients
4. Attacks bone, spinal cord, kidneys and causes bone marrow failure
  1. Kidney tubules are blocked up by protein containing antibody light chains
  2. Causes swelling of the tongue
5. Treatable but not curable
  1. Chemotherapy and radiotherapy used
  2. New agents - thalidomide and proteasome inhibitors (target protein degredation)

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Haematopoietic System Malignancies 2

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