PBL 32

Question 1

Overview of chronic myeloid leukaemia

1. Mechanism
2. Clinical manifestation
3. Risk factors
4. Diagnosis
5. Treatment

Answer 1

1. Mechanism
   - When a pluripotent stem cell undergoes malignant transformation and clonal myeloproliferation, leading to an overproduction of mature and immature granulocytes (neutrophil, basophil, eosinophil)
   - PHILADELPHIA: reciprocal translocation between chromosomes 9 and 22. Chromosome 9 with oncogene ABL, is translocated to chromosome 22 to the BCR gene. The oncogene Bcr-Abl produces the oncoprotein Bcr-Abl tyrosine kinase, an unregulated, cytoplasm-targeted tyrosine kinase that allows cell proliferation without being regulated by cytokines, allowing the cell to become cancerous.
2. Clinical manifestation
   - Untreated CML undergoes 3 phase:
3. Chronic phase: An initial indolent period that may last 5-6 years. Fatigue, weakness, weight loss, night sweats
4. Accelerated phase: Anaemia, thrombocytopenia, splenomegaly, increasing basophils
5. Blast phase: Accumulation of blasts in extra-medullary sites
6. Risk factors
   - Smoking
   - Chemicals
   - Cancer treatment
   - Congenital syndromes: down syndrome, Li Fraumeni
   - Family history
   - Gender
7. Diagnosis
   - Full blood count - CML patients have an >WBC count,

Question 2

What is leukaemia?

Answer 2

Group of cancers that usually begin in the bone marrow and result in high number of abnormal WBCs which are not fully developed (called blasts)

Question 3

General symptoms of leukaemia

Answer 3

• Bleeding and bruising problems
• Tired
• Fever
• Increased infection risk

Question 4

4 main types of leukaemia

Answer 4

1. Acute lymphoblastic leukaemia
2. Acute myeloid leukaemia
3. Chronic lymphocytic leukaemia
4. Chronic myeloid leukaemia

ACUTE LEUKAEMIA = Characterised by rapid increase in the number of immature blood cells. The crowding results from such cells makes the bone marrow unable to produce healthy blood cells. Most common in children

• Acute myeloid: cancerous change takes place in a type of marrow cell that normally goes on to form RBCs, some WBCs and platelets
• Acute lymphoblastic: cancerous change takes place in a type of marrow cell that normally goes on to form lymphocytes

CHRONIC LEUKAEMIA: characterised by the excessive build up of relatively mature, but still abnormal, WBCs. Typically takes months or years to progress, the cells are produced at a higher rate than normal, resulting in many abnormal blood cells
- Chronic lymphocytic: most involve B cells

Question 5

Common classes of chemotherapy drugs and mechanism of action

Answer 5

1. Alkylating agents (cyclophosphamide)
   - Bind covalently to DNA via alkyl group
   - Molecule binds either twice to one strand or once to both strands
   - If the cell tries to replicate the cross-linked DNA, the strands will break and the cancer cell will die as it cannot multiply
   - Work at ANY POINT of the cell cycle = cycle-independent
   - Dacarbazine = mono
   - Cyclophosphamide (nitrogen mustard) = di
2. Antimetabolites (5-fluorouracil)
   - Impede DNA and RNA synthesis
   - Similar structure to nucleotides or nucleobases but have altered chemical groups.
   - They stop purines and pyrimidines being added to thte DNA during S phase, stopping normal development and cancer cell division
   - Block enzymes required for DNA synthesis (prevent mitosis) or become incorporated into DNA or RNA (apoptosis)
   - Cell cycle dependent! (Only work in S phase)
3. Anti-microtubule agents (vinblastine)
   - Plant-derived chemicals that block cell division by preventing microtubule function (alpha and beta tubulin)
   - Some prevent microtubule formation others prevent dissociation
   - PREVENTS CANCER FROM COMPLETING MITOSIS, LEADS TO APOPTOSIS
4. Topoisomerase inhibitors (doxorubicin)

Question 6

Side effects of chemotherapy

Answer 6

• Fatigue
• Diarrhoea
• Nausea/vomiting
• Constipation
• Loss of appetite
• Sore mouth
• Anaemia
• Bruising and bleeding
• Increased risk of infection
• Fertility issues