INTRODUCTION TO LEUKAEMIA’S Flashcards
What is leukaemia?
o Characterised by malignant overproduction of white blood cells or their immature precursors. o 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.”
What are the 3 lineages of blood cells?
o Blood cells belong to 3 different lineages
- RBCs – formation is called erythropoiesis
- Lymphocytes lymphoid lineage
- Myeloid – forms the leukocytes
The green box are the mature cells which can be found in blood; the cells above are progenitors/ stem cells which are not mature enough to carry out different functions
Define pluripotent and self-maintaining
o Pluripotent- can give rise to cells of every blood lineage
o Self-maintaining- a stem cell can divide to produce more stem cells
What are progenitor cells?
Define unipotent
o Can divide to produce many mature cells
o But cannot divide indefinitely
o Eventually differentiate and mature
o Progenitor cells are at the top
o They are multipotent
o The cells further down are unipotent since they are committed to forming one type of cell only (i.e. committed to a lineage)
- Progenitor cells- Undifferentiated (multipotent): you cannot tell the difference between them morphologically because they do not show the characteristics of mature cells.
- Progenitor cells- Committed (unipotent): already committed as to what they will become when they generate mature cells
What 3 genetic changes can cause leukaemia?
o Activation of oncogenes and inactivation of tumour suppressor genes
o May involve genes similar to other malignancies e.g.
• RAS
• MYC
• P53 tumour suppressor
o But also some specific to the leukaemia’s, ones generated by chromosome translocations
o Chromosome translocations to generate novel (involve gene from 1 chromosome linked to gene from another chromosome) hybrid oncogenes e.g.
• BCR-ABL in CML
• PML-RARA in AML M4 – so PML has become linked by the translocation with another gene, RARA (retinoic acid receptor alpha)
• And many others
o Numerical chromosome changes e.g. • Monosomy – one copy of chromosome • Trisomy – 3 copies of the chromosome • Important for prognosis and treatment • Numerical changes are common in solid tumours but harder to karyotype on the, easier on leukaemia’s on blood cells
How is Leukaemia a clonal disease?
Define clonal
o All the malignant cells derive from a single mutant stem cell
o In normal haemopoiesis, many stem cells contribute to production of blood cells
o In leukemia, there is a mutation in one cell and often there is more than one mutation
o In clonal haemopoieses, all the leukemic cells derive from one mutant cell
o Clonal means a group of cells who are genetically the same
o Once a mutation has occurred in one cell, then all the cells in the leukemic clone are genetically identical and carry that mutation
o In leukaemia, a stem cell gets a mutation and this effects transcription factors. TFs are regulators of haematopoiesis.
o Oncogenic TFs drive progenitors to a pre-leukaemic state. They arrest the differentiation/ maturation of progenitor cells.
o A second hit (e.g. UV rays – a trigger for the oncogenic mechanisms) then induces full blown leukaemia – it causes high proliferation and low levels of development and apoptosis in the cells
o So you end up having a lot of new cells accumulate that are unable to die
o RUNX1 TF mutated in most cases of AML
How does leukaemia present itself?
o Varies between types of leukaemia
o But typically first presents with symptoms due to loss of normal blood cell production
• Commonest presentation is abnormal bruising due to lack of…
• Or repeated / abnormal infection due to neutrophils
• Sometimes just anaemia – reduced amount of RBCs
How can we diagnose it?
On image
What are the risk factors of leukemia?
o Exact cause is unclear. o Combination of predisposing factors. o Most cases of leukaemia are not associated with any identifiable precipitating cause o For some adult cancers: 1. Smoking 2. Drinking 3. Excessive exposure to sun 4. Overweight
o Radiation exposure
Acute radiation accidents
Atomic bomb survivors – have higher rates of leukaemia after several years
o Chemicals
e.g. industrial exposure to benzene
o Chemotherapy
Cancer chemotherapy (for other cancers) with alkylating agents (e.g. Busulphan) – common in acute myeloid leukaemia
o Immune system suppression can cause it to develop too
e.g. After organ transplant, immune system is suppressed so increased risk of developing leukaemia
o Viruses
Only one very rare example: HTLV-1 pre-disposes to adult T-cell leukaemia/lymphoma
o Age
The age related incidence is different in different types of leukaemia.
o Controversial – possible links to childhood leukaemia
Exposure to electromagnetic fields
Infections early in life
Mother’s age when child is born
Nuclear power stations,
Parent’s smoking history
Foetal exposure to hormones
Electric power lines,
Natural background radiation.
o Genetic factors
NOT usually hereditary
(except for some cases of Chronic Lymphocytic Leukaemia (CLL))
Some rare genetic diseases may predispose to leukaemia, e.g. Fanconi’s anaemia, Down’s syndrome
Genetic causes / risk factors
- Gene mutations involving oncogenes (activation) or/and tumour suppressors (inactivation).
- Involving genes common to other malignancies (TP53- Li-Fraumeni syndrome, NF1-Neurofibromatosis) or genes specific to leukaemia. It has been observed that the RAS pathway is mutated in certain types of leukaemia.
- Chromosome aberrations (i.e. something that is away from the normal):
Translocations (e.g. BCR-ABL in CML and PML-RAR in AML).
Numerical disorders (e.g. trisomy 21-Down syndrome).
- Can be due to inherited immune system problems too (e.g. Ataxia-telangiectasia, Wiskott-Aldrich syndrome) not a main consequence of genetic alteration.
How can we classify this disease?
Define Lymphocytic
Define Granulocytic
Define Myeloid
o Lymphocytic – involves mature lymphocytes
o Granulocytic – involves mature granulocytes/neutrophils
o Lymphoid- involving cells of the lymphocyte lineages
- Commonly B-cell,
- More rarely T-cell
o Myeloid- involving any of the non-lymphocyte blood cell lineages
- Commonly neutrophils or their precursors
- But can be erythroid, platelet, basophil lineages etc
o ‘Lymphoblastic’ and ‘lymphocytic’ (same applies for myelo-) used interchangeably
Define Acute Leukemia’s?
• Acute- means a disease having a rapid onset and short but severe course
• But acute leukaemia’s are defined as
- Undifferentiated leukaemia’s
- Characterised by immature white cells (blast cells)
• Myeloblasts and lymphoblasts are affected.
• So the acute leukameias affect the blasts – immature cells
Define Chronic Leukaemia’s?
• Chronic- means a disease persisting over a long time
• Chronic affects differentiated cells build up of mature white cells (cytes)
• Characterised by an increase number of differentiated cells -“differentiated leukaemia”.
• But chronic leukaemia’s are defined as
- Differentiated leukaemia’s
- Characterised by mature white blood cells
• The chronic leukaemias affect the progenitors – mature cells
What causes acute leukemia?
o Characterised by a large number of lymphoblasts (ALL) or myeloid blasts (AML) in bone marrow and blood- “undifferentiated leukaemia”.
- Normal cell proliferate à give a blast cell pool à these mature à mature cells have limited life span before they die
- If the cells fail to mature, they don’t become mature cells. So blast cell pool increase, typically in acute leukemia, if there’s not an increase in cell proliferation as there is a decrease in cell death that causes this increase in cell number. Decrease in cell death is failure of cells to mature, sitting in immature stage
Have a look at a bone smear of leukaemia?
On document
How can we diagnose?
- 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).
