Introduction to Leukaemia Flashcards by UNKNOWN T

Blood cancers

Leukaemia
Lymhphoma
Myeloma

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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.

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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)

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Differentiating cells within the haematopoietic process

-Haematopoietic stem cells

-Progenitor cells
>undifferentiated progenitor cells (multipotent)
>committed progenitor cells (unipotent)

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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

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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

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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

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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

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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

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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

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Genetic risk factors of leukaemia and heritance

Not usually hereditary (except for some cases of chronic lymphocytic leukaemia)

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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

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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

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Life-style related risk factors of leukaemia

For some adult cancers:

Smoking
Drinking
Excessive exposure to sun
Overweight

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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

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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)

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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

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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)

summary