Introduction to Leukaemia Flashcards
Blood cancers
Leukaemia
Lymhphoma
Myeloma
What is leukaemia?
a group of malignant disorders of haematopoietic stem cells characteristically associated with increased number of white blood cells in bone marrow and/or peripheral blood.
Blood cell lineages
Blood cells are divided into 3 lineages:
- Erythrocytes
- Cells of lymphoid lineage (B & T lymphocytes, natural killer cells involved in adaptive immune response)
- Cell of myeloid lineage (produces rest of leukocytes involved in innate immune response & blood clotting)
Differentiating cells within the haematopoietic process
-Haematopoietic stem cells
-Progenitor cells
>undifferentiated progenitor cells (multipotent)
>committed progenitor cells (unipotent)
Haematopoietic Stem Cells (HSCs)
· Pluripotent- can give rise to cells of every blood lineage
· Self-maintaining- a stem cell can divide to produce more stem cells
Characteristics of Progenitor Cells
· Not pluripotent anymore; either multipotent or unipotent
· Can divide to produce many mature cells
· But cannot divide indefinitely
· Eventually differentiate and mature
Types of progenitor cells
Undifferentiated Progenitor Cells (multipotent)
-can’t be differentiated between each other morphologically because they don’t show characteristics of mature cells
Committed Progenitor Cells (unipotent)
-committed to a specific lineage when they generate mature cells
Why is leukaemia considered a ‘clonal’ disease?
all the malignant cells derive from a single mutant stem cell (either a mutation in the haematopoietic stem cell or a progenitor cell):
- This mutation converts the cell into a stem cell with self-renewal ability
- This causes a pre-leukaemia status
- During development in the individual’s life, acquisition of another/second mutation is necessary to give rise to a full-blown leukaemia
- This causes abnormal levels of proliferation and cell survival, producing a leukaemia state
How does leukaemia first present?
Typically, first presents with symptoms due to loss of normal blood cell production (bone marrow suppression):
· Thrombocytopenia: purpura (bruising), epistaxis (nosebleed), bleeding from gums
· Neutropenia: Recurrent infections, fever
· Anaemia: lassitude, weakness, tiredness, shortness of breath
Aetiology of leukaemia
Exact cause of leukaemia is unclear.
Combination of predisposing factors:
- genetic risk factors
- lifestyle-related risk factors
- controversial risk factors
- environmental risk factors
Genetic risk factors of leukaemia and heritance
Not usually hereditary (except for some cases of chronic lymphocytic leukaemia)
Genetic risk factors of leukaemia
Gene Mutations involving oncogenes (activation) and/or tumour suppressor genes (inactivation)
-involving genes common other malignancies (e.g. TP53-Li-Fraumeni syndrome; NF1- Neurofibromatosis) or specific to leukaemia
Chromosome Aberrations
- translocations (e.g. BCR-ABL in CML)
- numerical disorders (e.g. trisomy 21- Down’s)
Inherited Immune System Problems
-e.g. Ataxia telangiectasia; Wiskott-Aldrich syndrome
Environmental risk factors of leukaemia
Radiation Exposure
· Acute radiation accidents
· Atomic bomb survivors
Exposure to Chemicals and Chemotherapy
· Cancer chemotherapy with alkylating agents (e.g. Busulphan)
· Industrial exposure to benzene
Immune System Suppression
· E.g. after organ transplant
Life-style related risk factors of leukaemia
For some adult cancers:
- Smoking
- Drinking
- Excessive exposure to sun
- Overweight
Controversial risk factors of childhood leukaemia
Possible link to childhood leukaemia (not proven):
- Exposure to electromagnetic fields
- Infections in early life
- Mother’s age when child is born
- Nuclear power stations
- Parent’s smoking history
- Foetal exposure to hormones
Leukaemia classification
Classified according to cell lineage (lymphoid or myeloid) and degree of terminal differentiation (acute or chronic).
Lymphoid:
-Acute Lymphoid/Lymphoblastic Leukaemia (ALL)
-Chronic Lymphoid/Lymphocytic Leukaemia (CLL)
Myeloid:
-Acute Myeloid/Myeloblastic Leukaemia (AML)
-Chronic Myeloid/Granulocytic Leukaemia (CML)
Acute Leukaemia
Undifferentiated leukaemia
Characterised by uncontrolled clonal and accumulation of immature white blood cells/multipotent progenitor cells (-blast)
- lymphoblasts (ALL) or myeloid blasts (AML) in bone marrow and blood
- very hard to distinguish because morphology is very similar
Sudden onset and short (weeks to months) but severe course
Chronic Leukaemia
- Differentiated leukaemia
- Characterised by uncontrolled clonal and accumulation of mature white blood cells/unipotent progenitor cells (-cyte)
- persists over time (years)
Compare the characteristics of acute and chronic leukaemia
What causes acute leukaemia?
- Blast cell pool is arrested and cells are not able to differentiate and mature.
- As a consequence, there is a lack of mature cells, and there is a big pool of blast cells.
- As the balance between cell proliferation and cell death is disrupted, there will be high levels of proliferation of blast cells and a lack of mature cells, causing acute leukaemia.
Symptoms of acute leukaemia
Typical symptoms of acute leukaemia are due to loss of normal blood cell production (bone marrow suppression):
· Thrombocytopenia: purpura (bruising), epistaxis (nosebleed), bleeding from gums
· Neutropenia: Recurrent infections, fever
Anaemia: lassitude, weakness, tiredness, shortness of breath
How is acute leukaemia diagnosed?
Peripheral Blood Blasts Test (PB):
-to check for presence of blasts and cytopenia
-if >30% blasts, acute leukaemia suspected
Bone Marrow Biopsy Test (BM):
-taken from pelvic bone and results compared with peripheral blood
Lumbar Puncture
-to determine if the leukaemia has spread to the cerebral spinal fluid
Acute Lymphoblastic Leukemia (ALL)
Prevalence of acute lymphoblastic leukaemia (ALL)
B & T cell leukaemia
-cancer of immature lymphocytes (lymphoblasts)
Commonest cancer of childhood 31%
-but overall still not very common
Treatment of acute lymphoblastic leukaemia (ALL) and outcome
Chemotherapy
-rare long term side effects
Outcome:
- 5 year event-free survival (EFS) of 87% in 2010.
- 1 in 10 of ALL patients relapse
- Remission in 50% after second chemotherapy treatment or bone marrow transplant
- poorer prognosis in adults because disease presents different cell or origin and different oncogene mutations
Acute Myeloblastic Leukaemia (AML)
Prevalence of acute myeloblastic leukaemia (AML)
Cancer of immature myeloid white blood cells/myeloblasts
Very rare
-70 children aged <16 y/o diagnosed in the UK every year
Treatment of acute myeloblastic leukaemia (AML) and outcome
Chemotherapy
Immunotherapy (monoclonal antibodies)
+/- allogenic bone marrow transplant
Outcome:
-5 year event free survival (EFS) of 50-60%
Chronic Lymphocytic Leukemia (CLL)
Large numbers of mature (clonal) lymphocytes in bone marrow and peripheral blood
Prevalence of chronic lymphocytic leukaemia
3,800 new cases diagnosed in UK every year (average age of diagnosis=70)
Symptoms of chronic lymphocytic leukaemia (CLL)
· Thrombocytopenia: purpura (bruising), epistaxis (nosebleed), bleeding from gums
· Neutropenia: Recurrent infections, fever
· Anaemia: lassitude, weakness, tiredness, shortness of breath
· Lymph node enlargement
· Hepatosplenomegaly
Treatment of chronic lymphocytic leukaemia (CLL) and outcome
Chemotherapy
Outcome:
- 5 year event free survival (EFS) of 83%.
- many patients survive >12 years
Chronic Myeloid/Granulocytic Leukaemia (CML)
Large numbers of mature myeloid white blood cells
Prevalence of chronic myeloid/granulocytic leukaemia (CML)
742 new cases diagnosed in the UK every year (peak rate=85-89 y/o)
Symptoms of chronic myeloid/granulocytic leukaemia (CML)
Often asymptomatic and discovered through routine blood tests
Treatment of chronic myeloid/granulocytic leukaemia (CML) and outcome
Targeted Therapy
-Imatinib (specifically inhibits BCR-ABL)
Outcome:
- 5 year event free survival (EFS) of 90%
- eventually progresses to accelerated phase and then blast crisis (allogenic bone marrow transplant needed)
Cause of 95% of chronic myeloid/granulocytic leukaemia
95% of cases of CML have a detectable Philadelphia chromosome (Ph’).
· This chromosome is the result of a balanced chromosomal translocation between the long arm of chromosome 9 and the long arm of chromosome 22.
Function of BCR Gene
(from chromosome 22): encodes a protein that needs to be continuously active
Function of ABL Gene
(from chromosome 9): encodes a protein tyrosine kinase whose activity is tightly regulated (auto-inhibition)
Consequence of balanced chromosomal translocation between chromosome 9 and 22
- The BCR and ABL genes come closer to one another, and the promoter of the BCR gene starts regulating the expression of the ABL oncogene.
- As a consequence of the fusion between these two genes (BCR-ABL oncogene), a fusion oncoprotein is produced which is going to be upregulated.
- The function of this oncoprotein will still belong to the ABL gene (tyrosine kinase activity), but upregulated by the promoter of the BCR gene.
Upregulated BCR-ABL oncoprotein causes:
increased tyrosine kinase, which results in:
- Proliferation of progenitor cells in the absence of growth factors
- Decreased apoptosis
- Decreased adhesion to bone marrow stroma
BCR-ABL Oncogene targeted therapy
Imatinib (Glivec®, ST1571)
- inhibits BCR-ABL
- causes apoptosis of CML cells
- remission induced in more patients, with greater durability and fewer side effects
Mechanism of action of Imatinib
ABL is a tyrosine kinase which uses ATP to phosphorylate its substrate.
Imatinib is a small molecule that binds the small pocket where ATP usually binds the ABL gene and therefore acts as a competitor.
By binding to the small pocket, ATP molecules can’t bind ABL anymore, and ABL can’t phosphorylate the substrate. As a consequence, there is activation of apoptosis of CML cells.
Disadvantage of Imatinib
some patients become drug resistant (need other types of treatment)
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