Introduction to Leukaemia Flashcards
What are the three major blood cancers?
- Leukaemia
- Lymphoma
- Myeloma
What is Leukaemia?
Malignant disorder of the haematopoietic stem cells associated with increased white blood cells in bone marrow and peripheral blood
What are the features of haematopoietic stem cells?
- Pluripotent = Give rise to blood cells of every lineage
- Self-Maintaining = A stem cell that can divide and produce more stem cells
What are the features of progenitor cells?
- Can divide to produce many mature cells
- Can be multipotent/unipotent
- Eventually differentiate and mature
- But cannot divide indefinitely!!!
What are the two types of progenitor cells?
Undifferentiated (Multipotent) = Have the ability to form different types of blood cells Committed (Unipotent) = Committed to a particular cell line and produce one type of blood cell
What does it mean by saying Leukaemia is a clonal disease?
All malignant cells derive from a mutation in a single stem cell (either a mutation in the haematopoeitic stem cell or a progenitor cell)
- Mutation converts cell into stem cell with self-renewal abillity
- = causes the pre-leukaemia status
- During development in individuals life acquisition of another/second mutation is necessary to give rise to full-blown leukaemia
- = causes abnormal levels of proliferation + cell survival producing a leukaemia state
What are the general symptoms of leukaemia that you first present?
Will vary depending on the type of leukaemia but typically first you will present with symptoms due to loss of normal blood cell production
- Abnormal bruising (thrombocytopenia, epistaxis (nose bleed) and bleeding from gums
- Repeating abnormal infection (Neutropenia, fevers)
- Sometimes anaemia (this is because the bone marrow is overproducing white cells and there is little room for normal RBC’s to develop)
What is the aetiology of leukaemia?
- Exact cause of leukaemia is unclear
- It is a combination of predisposing factors including:
- Genetic risk factors, environmental factors and lifestyle related risk factors (polyetiologic)
Genetic factors of leukaemia
- NOT USUALLY HEREDITARY except for CLL and rare hereditary diseases which may predispose leukaemia like Fanconi’s anaemia + Down’s Syndrome
What can genetic causes of leukaemia be explained by?
-
Genetic mutations involving oncogenes (activation) or/and tumour suppressors (inactivation) lead to leukaemia
- Involving genes common to other malignancies (Tp53-Li-Fraumeni Syndrome, NF-1 Neurofibromastosis) or specific leukaemia
-
Chromosome Aberrations:
- Translocations (e.g BCR-ABL in CML)
- Numerical disorders (e.g trisomy 21-Down Syndrome)
-
Inherited immune system problems
- e.g Ataxia-telangiectasia, Wiskott-Aldrich syndrome)
What are environmental risk factors associated with leukaemia?
-
Radiation exposure
- Acute radiation accidents
- Atomic bomb survivors
-
Exposure to chemicals + chemotherapy
- Cancer chemotherapy with alkylating agents (e.g Busulphan)
- Industrial exposure to benzene
-
Immune system suppression
- E.g After organ transplant
What can leukaemia be split into?
- Acute Lymphoblastic leukaemia (ALL)
- Acute Myeloblastic Leukaemia (AML)
- Chronic Lymphocytic Anaemia (CLL)
- Chronic Granulocytic/Myeloid Leukaemia (CML)
What is the difference between acute and chronic leukaemia?
Acute (undifferentiated) = Characterised by rapid onset and short but severe course, undifferentiated leukaemia, characterised by untrolled clonal accumulation of immature WBC’s known as myeloblasts/lymphoblasts
Chronic (differentiated) = Persists over a long period of time, differentiated leukaemia, characterised by uncontrolled clonal and accumulation of mature (cyte) blood cells
Describe the age onset, duration and wbc count in acute and chronic leukaemia
Describe undifferentiated leukaemia
- Acute leukaemia can also be termed undifferentiated leukaemia
- Characterised by a large number of lymphoblasts (ALL) or myeloblasts (AML) in bone marrow and blood
- In a normal individual pool of blast cells which differentiate and become mature will die via apoptosis and necrosis
- In leukaemia there is an arrest in the blast cell pool, cells are unable to differentiate and there will be a lack of mature cells = cause acute leukaemia
What are the general symptoms of acute leukaemia?
- They are all related to bone marrow suppression
- Thrombocytopenia: purapura (bruising), epitaxis (nosebleed), bleeding from gums Neutropenia: Recurrent infections, fever
- Anaemia: Iassitude, weakeness, tiredness, shortness of breath
How do we treat acute lymphoblastic leukaemia (ALL)?
- Treatment: Chemotherapy. Long term side effects are rare
- Outcome: 5 year event-free survival (EFS) of 87% in 2010. 1 out of 10 ALL patients relapse. Remission in 50% percent of them after second chemotherapy treatment or bone marrow transplant.
Who is most affected by chronic lymphocytic leukaemia (CLL)? And what are the symptoms of it?
- Prevalence = greater association with adults (Average diagnosis aged 70)
- Symptoms
- Thrombocytopenia: purpura, epistaxis, bleeding from gums
- Neutropenia: Recurrent infections, fever
- Anaemia: lassitude, weakness, tiredness, shortness of breath
- Lymph node enlargement
- Hepatosplenomegaly
What have 95% of the cases of CML been due to?
- 95% of cases have a Philadelphia Chromosome
- This is a balanced chromosomal translocation between long arm of chromosome 9 and 22
- When a translocation happens between these two genes the BCR promoter will start regulating the ABL oncogene = fusion oncoprotein
What occurs as a consequence of this balanced chromosomal translocation?
- The BCR and ABL genes will come closer together, the promoter of the BCR gene will sart to regulate the expression of the ABL oncogene.
- As a consequence = fusion of these two genes (BCR-ABL oncogene) a fusion oncoprotein is produced that is upregulated
- The function of this protein will still belong to the ABL gene (tyrosine kinase activity) but upregulated by the promoter of the BCR gene
How does Imatinib work?
Specifically inhibits ABL (a tyrosine kinase) by blocking a pocket where ATP would bind Causes apoptosis of CML cells
Describe a potential application of diagnosis of CML
- Diagnosis
- 95% of cases of CML have a detectable ‘Ph’ chromosome
- Probe binding DNA which is attached to fluorphores
- Red flurophore is attached to probe which binds ABL gene
Green fluorphore is attached to probe which binds BCR gene
- Red flurophore is attached to probe which binds ABL gene
- Normal conditions genes will be separated therefore no fluorescence
- However, in the presence of the Ph chromosome from translocation leading to gene fusion there will be fluorescence
- ALLOWS US TO DETECT minimal residual disease – if after treatment there is still fluorescence it means that leukaemia hasn’t been cured
What do your monoblasts differentiate into?
Granulocytes (eosinophils, neutrophils, basophils) and monocytes
