intro to leukaemia Flashcards
another word for white blood cells?
leukocytes
name some types of leukocytes
neutrophils, monocytes, basophils
how can leukaemia be detected?
high levels of these white cells in blood
define leukaemia
“malignant disorders of haematopoietic stem cells characteristically associated with increase number of white cells in bone marrow or/and peripheral blood.”
what is haemoatopoiesis?
formation of blood cells
how many lineages are blood cells are divided into and what are their names?
three different lineages
-erthrocytes, lymphoid lineage, myeloid lineage
name some stages of haemoatopoiesis
multipotential hematopoetic stem cell (hemocytoblast) splits into a common myeloid progenitor and common lymphoid progenitor
common myeloid progenitor goes into megakaryocyte, proerythroblast and myeloblast
characteristics of 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
-pool Is never depleted because the daughter cells are also HCSs
characteristics of progenitor cells?
Can divide to produce many mature cells
But cannot divide indefinitely - they have a lifespan
Eventually differentiate and mature
not pluripotent but can be multi and unipotent
can progenitor cells be pluripotent?
no, but they can be multi and unipotent
name the 2 types of progenitor cells and the differences between them
undifferentiated/multipotent
can’t tell the difference between them morphologically because they do not show the characteristics of mature cells
committed/unipotent
already committed to what they will become when they generate mature cells
can’t distinguish between the different types of differentiated progenitor cells based on morphology
what type of disease is leukaemia and how does it occur?
a clonal disease - all the malignant cells derive from a single mutant stem cell
one of the cells will acquire a mutation, stem cells that have self renewl ability converted to a pre-leukamemia status
a second mutation occurs later which gives rise to the full-blown leukaemia
Incidence rate of leukaemia?
associated with age, represents 31% of children cases
around 38% of total cancers are leukaemia in people aged 75 and over
presentation of leukaemia
varies from person to person
Typically first presents with symptoms due to loss of normal blood cell production
Abnormal bruising-commonest
Repeating abnormal infection
Sometimes anaemia
once leukaemia has been detected what should happen?
important to carry out analysis e.g. NGS to assess the molecular profile
we can also detect chromosomal abnormality and identification of the subtype of leukaemia, gives us useful info for the treatment process
cause of leukaemia?
exact cause is unclear
-combination of predisposing factors, genetic and environmental factors
genetic risk factors of leukaemia?
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
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).
- Numerical disorders (e.g. trisomy 21-Down syndrome).
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
lifestyle-related risk factors of leukaemia?
Smoking, drinking, Excessive exposure to sun
and being overweight
controversial risk factors of leukaemia?
Possible link to childhood leukaemia
- Mother’s age when child is born
- Infections early in life
- Exposure to electromagnetic fields
- Nuclear power stations
- Parent’s smoking history
- Foetal exposure to hormones
how is leukaemia classified?
4 types of leukaemias, grouped into two main categories
classified based on type of lineage – lymphoid or myeloid
also based on the type of cause – acute and chronic depending on whether it’s an early age onset and sudden or a later onset and gradual, respectively
acute leukaemia?
rapid onset and short but severe course
(ALL, AML)
- Undifferentiated leukaemia
- Characterised by uncontrolled clonal and accumulation of immature white blood cells (-blast, e.g. myoblast or lymphoblast)
Chronic leukaemia?
persisting over a long time
(CLL, CML)
- Differentiated leukaemia
- Characterised by uncontrolled clonal and accumulation of mature white blood cells (-cyte)
ALL
Acute Lymphoblastic Leukaemia
AML
Acute Myeloblastic Leukaemia
CLL
Chronic Lymphocytic Leukaemia
CML
Chronic myeloid Leukaemia
acute vs chronic?
AGE
acute: Mainly children
chronic: Middle age and elderly
ONSET
acute: Sudden
chronic: Insidious
DURATION
acute: weeks to months
chronic: years
WBC COUNT
acute: variable
chronic: high
classifications of acute leukaemia?
lymphoid
-Acute Lymphoblastic Leukaemia (ALL)
myeloid
-Acute Myeloblastic Leukaemia (AML)
is ALL common?
Overall its not very common, but out of the subtypes it is the most common cancer
75% ALL
20% AML
what is acute luk characterised by?
characterized by large number of lymphoblasts (ALL) or myeloid blasts (AML) in bone marrow and blood- “undifferentiated leukaemia”
difficult to distinguish because their morphology is very similar
what happens under normal conditions with blast cells and what happens in leukaemia?
normal conditions
-pool of blasts cells proliferate and differentiate and become mature and die eventually
leukaemia
-cells unable to differentiate and cannot mature, so there are a large pool of blast cells -the balance between new cells and cell death is broken, and there is a lack of mature cells
typical symptoms of acute luk?
typical symptoms are due to bone marrow suppression
- Thrombocytopenia: purpura (bruising), epistaxis (nosebleed), bleeding from gums
- Neutropenia: Recurrent infections, fever
- Anaemia: lassitude, weakness, tiredness, shortness of breath
diagnosis of acute luk (tests)
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).
describe Acute Lymphoblastic Leukaemia (ALL)
Prevalence: Commonest cancer of childhood (overall still not very common).
Origin: Cancer of immature lymphocytes (lymphoblasts or blasts).
Classification: B-cell & T-cell leukaemia
Treatment: Chemotherapy. Long term side effects are rare
Outcome: 5 year event-free survival (EFS) of 87% in 2010. 1 out of 10 ALL patients relapse. Remission in 50% percent of them after second chemotherapy treatment or bone marrow transplant
why does adult ALL have a poorer prognosis?
because disease presents different cell of origin and different oncogene mutations
describe Acute Myeloblastic Leukaemia (AML)
Prevalence: 70 children aged ≤16 y/o diagnosed in the UK every year (very rare)
Origin: Cancer of immature myeloid white blood cells
Classification: based on FAB system (French-American-British): M0-M7
Treatment: Chemotherapy, monoclonal antibodies (immunotherapy) +/- allogeneic bone marrow transplant
Outcome: 5 year event-free survival (EFS) of 50-60%.
does ALL or AML have a worse outcome?
AML, but it still has a high survival
in AML are the blasts difficult to distinguish and whats the consequence of this?
the blasts are difficult to distinguish morphologically, so cytological analysis needs to be undertaken for the identification of the cells
- in this case, there is also targeted therapy with the use of monoclonal antibodies
chronic leukaemia types?
lymphoid
-Chronic Lymphocytic Leukaemia
(CLL)
myeloid
-Chronic Granulocytic Leukaemia
(CML)
what is chronic luk characterised by?
characterised by an increase number of differentiated cells -“differentiated leukaemia”.
describe Chronic Lymphocytic Leukaemia (CLL)
Prevalence: 3,800 new cases diagnosed in the UK every year (average diagnosis age= 70).
Origin: 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: Regular chemotherapy to reduce cell numbers.
Outcome: 5 year event-free survival (EFS) of 83%. Many patients survive >12 years.
Hepatosplenomegaly
enlargement of the liver (and lymph nodes)
does acute or chronic affect older peoples more?
chronic affects people much older than acute leukaemia
describe Chronic Myeloid/Granulocytic Leukaemia (CML)
Prevalence: 742 new cases diagnosed in the UK every year (peak rate = 85-89y/o)
Origin: Large numbers of mature myeloid white blood cells.
Symptoms: Often asymptomatic and discovered through routine blood tests.
Diagnosis: Very high white cells count (neutrophilia) in blood and bone marrow, presence of Philadelphia chromosome
Treatment: Targeted therapy: Imatinib.
Outcome: 5 year event-free survival (EFS) of 90%. Eventually progresses to accelerated phase and then blast crisis.- allogeneic bone marrow transplant. Targeted therapy is efficient and there is a high survival rate
is CLL or CML more prevalent?
CML less prevalent than CLL
why does the Philadelphia chromosome form?
forms as a result of chromosomal translocation
what do 95% of cases of CML have?
a detectable Philadelphia chromosome
-a balanced translocation between the short arm of chromosome 9 and long arm of chromosome 22
means the BCR gene is next to the ABL gene
BAR and ABL - whats the consequence of the translocation?
BCR: encodes a protein that needs to be continuously active
ABL encodes a protein tyrosine kinase whose activity is tightly regulated (auto-inhibition)
BCR-ABL protein has constitutive (unregulated) protein tyrosine kinase activity
when this translocation happens, the genes come close to each other and the BCR starts regulating the expression of ABL
The fusion oncoprotein will be upregulated by the promoter of the BCR gene
consequence of unregulated BCR-ABL= ?
tyrosine kinase activity that causes:
Proliferation of progenitor cells in the absence of growth factors
Decreased apoptosis
Decreased adhesion to bone marrow stroma
probes and BCR and ABL gene?
Red fluophore binds to the ABL gene whereas green binds to BCR
When there is no chromosomal translocation, we shouldn’t see the probes together
However, after gene fusion or translocation, the green and red probes are close together and overlap
CML therapy?
Therapy: Drugs that specifically inhibit BCR-ABL. e.g. Imatinib (Glivec®, STI571). Cases negative for BCR-ABL require different therapy
Imatinib?
small molecule inhibitor that targets Abl –CML treatment - binds to the small pocket where Atp should bind so it acts as a competitive inhibitor – preventing ABL from binding so it cannot phosphorylate its substrate, causing apoptosis of the CML cells
Inhibits BCR-ABL but not most other tyrosine kinases
Remission induced in more patients,
with greater durability and fewer
side effects
Some patients become drug resistant
summary of luk?
Leukaemia is a cancer of the blood cells that can be classified according to cell linage (lymphoid or myeloid) and degree of terminal differentiation (acute or chronic).
Acute leukaemia has an earlier onset being the commonest cancer of the childhood. Evolves rapidly and requires prompt intervention with chemotherapy.
Chronic leukaemia is a later onset disease that generally progresses in indolent manner.
Targeted therapies are emerging in order to treat the disease based on the genomic alterations. e.g. Imatinib to treat chronic myeloid leukaemia (CML) BCR-ABL+.
