19. Intro to Leukaemias Flashcards
What is leukaemia?
- Leukaemia (“leuk” = white, “emia” = blood): “malignant disorders of haematopoietic stem cells characteristically associated with increase number of white cells in bone marrow or/and peripheral blood.”
- Higher number of WBCs
- There is distorted proliferation and development of leukocytes and their precursors in bone marrow and/or peripheral blood.
- It is a clonal disease- all the malignant cells derive from a single mutant stem cell.
What are 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
What are progenitors cells?
- Can divide to produce many mature cells
- But cannot divide indefinitely
- Eventually differentiate and mature
There are 2 types:
- UNDIFFERENTIATED:
- (multipotent): you cannot tell the difference between them morphologically because they do not show the characteristics of mature cells.
- DIFFERENTIATED:
- (unipotent): already committed as to what they will become when they generate mature cells
Leukaemia is a clonal disease. Expand,
What is the presentation of leukemia?
- Varies between types of leukaemia
- Typically first presents with symptoms due to loss of normal blood cell production
- Abnormal bruising-commonest
- Repeating abnormal infection
- Sometimes anaemia
What is the aetiology of leukaemia?
- Exact cause is unclear. Most cases not associated with any identifiable precipitating cause.
- Polyetiologic disease: combination of predisposing factors.
What are genetic risk factors of leukaemia?
1) Gene mutations involving oncogenes (activation) or/and tumour suppressors (inactivation).
- Involving genes common to other malignancies (TP53- Li-Fraumeni syndrome, NF1-Neurofibromatosis) or specific to leukaemia.
2) Chromosome aberrations:
- Translocations (e.g. BCR-ABL in CML and PML-RAR in AML).
- Numerical disorders (e.g. trisomy 21-Down syndrome).
3) Inherited immune system problems (e.g. Ataxia-telangiectasia, Wiskott-Aldrich syndrome).
What are the environmental risk factors associated with leukaemia?
1) Radiation exposure
- acute radiation accidents
- atomic bomb survivors
2) Exposure to chemicals and chemotherapy
- Cancer chemotherapy with alkylating agents (e.g. Busulphan)
- e.g. Industrial exposure to benzene
3) Immune system suppression
- e.g. After organ transplant
What are the lifestyle-related risk factors associated with leukaemia?
- smoking
- drinking
- excessive exposure to sun
- overweight
What are the possible link to childhood leukaemia?
- exposures to electromagnetic fields
- infections early in life
- mother’s age when child is born
- nuclear power stations
- parents smoking history
- foetal exposure to hormones
Expand on acute disease and acute leukaemia.
- Acute disease: rapid onset and short but severe course.
- Acute leukaemia:
- Undifferentiated leukaemia
- Characterised by uncontrolled clonal and accumulation of immature white blood cells (-blast)
- and so can be called:
- Acute LymphoBLASTIC Leukaemia (ALL)
- Acute Myeloblastic Leukaemia (AML)
Expand on chronic disease and chronic leukaemia.
- Chronic disease: persisting over a long time.
- Chronic leukaemia:
- Differentiated leukaemia
- Characterised by uncontrolled clonal and accumulation of mature white blood cells (-cyte)
*and so can be called:
- Chronic LymphoCYTIC Leukaemia
(CLL)
- Chronic GRANULOCYTIC Leukaemia
(CML)
What are the main differences between acute and chronic?
- AGE: ~ acute is mainly in children, and chronic in middle age and eldery
- ONSET ~ acute is sudden, and chronic is insidious
- DURATION ~ acute is weeks-months, and chronic is years
- WBC COUNT ~ acute is variable, and chronic is high
What is acute leukaemia characterised by?
Characterized by a large number of lymphoblasts (ALL) or myeloid blasts (AML) in bone marrow and blood- therefore “undifferentiated leukaemia”.
What are the typical symptoms of acute leukaemia?
- Typical symptoms due to bone marrow suppression:
- Thrombocytopenia: purpura (bruising), epistaxis (nosebleed), bleeding from gums.
- Neutropenia: Recurrent infections, fever.
- Anaemia: lassitude, weakness, tiredness, shortness of breath.
ALSO:
- night sweats
- swelling of lymph nodes
- spleen enlargement
What is the diagnosis of acute leukaemia?
- Peripheral blood blasts test (PB): to check for presence of blasts and cytopenia. >30% blasts are suspected of acute leukaemia.
- Bone marrow test/biopsy (BM): taken from pelvic bone and results compared with PB.
- Lumbar puncture: to determine if the leukemia has spread to the cerebral spinal fluid (CSF).
Methods of molecular and pathophysiological characterisation.
- Cytomorphology ~ Staining and observation of cells microscopically
- Immunophenotyping~Use different antibodies that attach to different cell markers
- Next Generation Sequencing (NGS)
- Fluorescence in situ Hybridation (FISH)
~Can establish genetic and genomic profile of the cells - Flow cytometry ~ Find different types of cells in sample
Molecular and pathophysiological characterisation of acute leukaemia.
- Many chromosome translocations
- Involve genes for transcription factors
- Chromosome abnormalities also help determine prognosis and response to treatment
What is the best way to differentiate between ALL and AML?
- As the symptoms are the same ~ best way to differentiate between ALL and AML is by performing all the diagnostic assays (especially bone biopsy)
What is chronic leukaemia characterised by?
Characterised by an increase number of differentiated cells “differentiated leukaemia”.
Summary of CLL
- Large numbers of mature (clonal) lymphocytes in bone marrow and peripheral blood.
- Symptoms: Recurrent infections due to neutropenia, and suppression of normal lymphocyte function, anaemia, thrombocytopenia, lymph node enlargement, hepatosplenomegaly.
- Treatment: Controlled by regular chemotherapy to reduce cell numbers.
- Outcome: 5 year event-free survival (EFS) of 83%. Many patients survive >12 years.
Summary of CML
- Large numbers of mature myeloid white blood cells.
- Symptoms: Often asymptomatic and discovered through routine blood tests; anaemia; fatigue; breathlessness; splenomegaly; LU quadrant fullness or pain; weight loss; and other less common.
- Diagnosis: Very high white cells count (neutrophilia) in blood and bone marrow, presence of Philadelphia chromosome or BCR-ABL gene rearrangements.
- Treatment: controlled (but not cured) with chemotherapy. Imatinib.
- Outcome: 5 year event-free survival (EFS) of 90%. Eventually progresses to accelerated phase and then blast crisis.- allogeneic bone marrow transplant.
Expand on BCR-ABL oncogene.
- Balanced translocation t(9;22)(q34;q11) ~ between the long arm of chromosome 9 and 22.
- p210 Bcr-Abl is found in CML
- p185 Bcr-Abl is found in ALL
Function of Bcr and Abl, and then the combined function.
NORMALLY:
- BCR: encodes a protein that acts as a guanine nucleotide exchange factor for Rho GTPase proteins
- ABL encodes a protein tyrosine kinase whose activity is tightly regulated (auto-inhibition)
- BCR-ABL protein has constitutive (unregulated) protein tyrosine kinase activity ~ when combined, the ABL bit loses its promoter and the beginning bit where it is regulated. – it will also lose its auto-inhibition and will be controlled by the first part of the BCR gene.
- upregulated protein kinase activity
