Haematopoietic System Malignancies 2

Haematopoietic System Malignancies 2

1. Lymphomas

   • Malignancy of lymph nodes
   • Hodgkins Lymphoma
   • Non-Hodgkin's Lymphoma
     • Diffuse large B cell lymphoma
     • Follicular lymphoma
     • Lots of others

2. Hodgkin's Disease

   • Often seen in young adults
   • Epstein-Barr virus is often integrated in malignant cells
   • Reed-Sternberg cells are malignant cells - surrounded by a sea of normal immune cells
   • Curable with chemotherapy/radiotherapy in most cases

3. Non-Hodgkin's Lymphoma

   • Mantle cell lymphoma
   • Small lymphocytic lymphoma
   • Follicular lymphoma
     • Indolent (slow growing) but curable
     • 10 year median survival
     • Patients present with lymphadenopathy
     • t(14;18) present in 90% of cases
       • Increases expression of BCL2 (anti-apoptosis protein)
         • Translocation puts BCL2 near immnoglobulin heavy chain gene
       • BCL2 inhibitors in clinical trials
   • Diffuse large B cell lymphoma
     • Most common
     • Lymph node replaced by large sheets of lymphoma cells
       • Large cells in diffuse sheets
     • Potentially curable
       • Monoclonal antibody therapy
         • Cells express CD20
         • Rituximab (antibody against CD20) kills lymphoma cells
           • Signal for apoptosis via complement cascade and MAC
             • Cells engulfed by macrophages
     • Aggressive

4. Epigenetic Regulation of Gene Expression

   • EZH2 methylates K27, inhibiting transcription
     • Gain of function in 27% follicular lymphoma
     • Both mutations reduce transcription
   • MLL2 methylates K4, increasing transcription
     • Loss of function of MLL2 in 90% follicular lymphomas

5. Chronic Lymphocytic Leukaemia (CLL)

   • Lymphoma of the blood/bone marrow
   • Caused by chronic proliferation of mature B cells
   • Usually presents with abnormal blood tests (discovered in routine test)
     • Very high white blood cells count - 200 (normal is 10)
   • Can present with lymphadenopathy
   • B cell activation
     • Antigen binds
       • Lyn kinase phosphorylates Syk kinase
         • Activates Bruton tyrosine kinase
           • Phosphorylates Plcg
             • Activates DAG and IP3
               • Increases Ca2+
                 • Proliferation and survival via Nf-kappaB
     • Lyn kinase, Syk kinase and Bruton tyrosine kinase all increased in CLL
       • Bruton tyrosine kinase inhibitors are in late stage clinical trials - have efficacy

6. Myeloma

   • Common
   • Plasma cells have become malignant
   • Produce an antibody which forms a monoclonal band in serum electrophoresis
     • Not present in normal patients
   • Attacks bone, spinal cord, kidneys and causes bone marrow failure
     • Kidney tubules are blocked up by protein containing antibody light chains
     • Causes swelling of the tongue
   • Treatable but not curable
     • Chemotherapy and radiotherapy used
     • New agents - thalidomide and proteasome inhibitors (target protein degredation)