intro to leukaemia Flashcards
What is leukaemia?
Malignant disorders of haemtopoietic stem cells characteristically associated with increased number of white cells in the bone marrow and/or peipheral blood.
What three lineages are all blood cells divided into?
Red blood cell/ erythrocytes - oxygen carrying cells, released into blood
Lymphocytes, derived from common lymphoid progenitors - B cells, T cells and natural killer cells
Cells of myeloid lineage – granulocytes, karyocytes, macrophages. Derived from common myeloid progenitors, involved in innate immune system and blood clotting
What two types of progenitor cells are there?
Undifferentiated progenitor cells (multipotent): can’t tell difference between them morphologically, don’t show characteristics of mature cells
- give rise to two different lineages
Progenitor cells - committed (unipotentt): committed to what they’ll become
- can only give rise to one type of blood cell
What can drive progenitors or HSCs to pre-leukemic stage?
Oncogenic transcription factors.
Secondary mutation required to induce full blown leukaemia through increased survival and proliferation.
malignant cells derived from single mutant stem cell.
What is the incidence of leukaemia?
Related to AIDS, highest incidence in older people.
in UK 2013-2015, 4/10 new cases were in people 75+
rates higher in males than females in older age groups
What is the presentation of leukaemia?
Varies between types.
Symptoms:
Abnormal bruising commonest
Repeating abnormal infection due to absence of normal white cells and immune power to fight disease
Sometimes anaemia due to reduced production of RBC – symptoms like fatigue, shortness of breath
How is leukaemia diagnosed?
Extract biopsy from bone marrow,
- Blast mature cells
- Light coloured RBC
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 leukaemia has spread to cerebral spinal fluid
After estabilishing leukaemia it must be characterised
What is used to characterise leukaemia?
Cell surface markers
Cytomorphology of cells
Using next gen seq to find mutations that may have caused leukaemia
Flow cytometry
Immunophenotyping
Fluorescence in situ hybridisation
Methods done to try to detect different cellular markers and detect mutations which are characteristic
What are the genetic risk factors of leukaemia?
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
Chromosome aberrations
- Translocations (e.g BCR-ABL in CML) give rise to new chromosome, triggered factor of 95% of chronic myeloid leukaemia’s
- All leukaemia’s can be associated with numerical disorders (e.g trisomy 21-Down syndrome)
Inherited immune system problems (e.g Ataxia-telangiectasia, Wiskott-Aldrich syndrome)
What are the 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
What are the lifestyle releated risk factors of leukamia?
Smoking
Drinking
Excessive exposure to sun
Overweight
other risk factors:
Exposure to electromagnetic fields
infections early in life
nuclae power stations
foetal exposure to hormones
Classification of leukaemia
What is acute leukaemia?
Rapid onset and short but severe course
Undifferentiated leukaemia, characterised by uncontrolled clonal and accumulation of immature white blood cells (blast)
Bone marrow and blood sample has high number of blast cells.
What is chronic leukaemia?
Persisting over a long time.
Differentiated leukaemia.
Characterised by uncontrolled clonal and accumulation of mature white blood cells (-cyte)
Affects cells that have already differentiated, unipotent.
What is the difference between acute and chronic leukaemia?
Age: children in acute, elderly in chronic
Onset: sudden, insidious
Duration: weeks to months, years
WBC: variable, high
What are the two types of acute leukaemia?
Acute lymphoblastic leukaemia (ALL)
Acute myeloblastic leukaemia (AML)
- commonest type of cancer in childood
- 31% of total cancers in children, 75% cases ALL, 20% AML
- characterised by large numbers of lymphoblasts or myeloid blasts in bm and blood
- arresst of mature process, breaks balance between proliferation and cell death
What are the symptoms of acute leukaemia?
Due to BM suppression:
Thrombocytopenia (low platelets): purpura (bruising), epistaxis (nosebleed), bleeding from gums. Are the most common symptoms.
Neutropenia (low neutrophils): recurrent infections and fever
Anaemia: lassitude, weakness, tiredness, shortness of breath
What is the origin of chronic lymphocytic leukaemia?
What are the symptoms?
What is treatment?
- Large numbers of clonal lymphocytes in BM and blood.
2.
Recurrent infections due to neutropenia
Suppression of normal lymphocyte function
Anaemia
Thrombocytopenia
Lymph node enlargement
Hepatosplenomegaly
3.
Regularly chemotherapy to reduce cell numbers
What is the origin of Chronic myeloid/granulocytic leukaemia?
Symptoms
Treatment
- Large number of mature myeloid white blood cells
- Asymptomatic, discovered through blood tests - high white blood cell count (neutrophilia) and philadelphia chromosome
- targeted therapy , imatinib.
What is BCR?
Encodes a protein that needs to be continously active.
Its promoter is strong and active, promotes permanent transcription of the gene.
What is ABL?
Encodes a protein tyrosine kinase whose activity is tightly regulated (auto-inhibition)
A proto-oncogene.
Tyrosine kinase needs ATP molecules in order to phosphorylate its substrates.
How does the BCR-ABL oncogene come about?
Translocation brings ABL gene under transcriptional regulation of BCR promoter.
Promoter controls transcription of ABL gene
therefore BCR-ABL protein has constitutive (unregulated) protein tyrosine kinase activity
What does unregulated BCR-ABL activity cause?
Tyrosine kinase activity causes:
- Proliferation of progenitor cells in the absence of growth factors
- Decreased apoptosis
- Decreased adhesion to bone marrow stroma
Triggers leukaemia
How is FISH used when diagnosising chronic myeloid leukaemia?
95% of CML have detectable Ph’ chromosome
FISH checks for Ph’ chromosome
Use of two probes, red = ABL gene, green = BCR gene
Ph’ chromosome, two chromosomes are fused, see both colours
also used in detection of minimal residual disease
How does Imatinib work?
Small molecule inhibitor, targets ABL-CML treatment
Inhibits continuously active tyrosine kinase activity of fusion protein
ABL gene contributes with tyrosine kianse activity, needs ATP to phosphorylate substrates to make it active
Imatinib competes with ATP, binds to BCR-ABL, preventing ATP from binding, can’t phosphorylate tyrosine
Oncogene not able to activate downstreamt pathways
