Introduction to Leukaemia

Question 1

Define Leukemia

Answer 1

This is a group of malignant disorders of hematopoietic stem cells characteristically associated with increase number of white cells in bone marrow /peripheral blood

Question 2

What cells does Leukemia affect ?

Answer 2

Lymphocytes
Neutrophils 
Lymphocyte
Monocyte 
Platelets

Question 3

What are hematopoietic stem cells (HSCs)

Answer 3

These stem cells are multipotent meaning they can give rise to cells of every blood lineage

Self maintaining -Stem cell can divide to produce more stem cells

When they divide they can be asymmetric or symmetric.

Following asymmetric division it forms more differentiated cells with less potency capacity

Question 4

What are progenitor cells ?What are formed from haematopoietic stem cells?

Answer 4

Haematopoietic stem cells can produce :
Common myeloid progenitor and Common lymphoid progenitor

• Can divide to produce many mature cells
• Cannot divide indefinitely
• Eventually differentiate and mature

Question 5

What types of progenitor cells are there ?

Answer 5

1. Undifferentiated (multipotent)

You cannot differentiate between myeloid /lymphoid because they do not show the characteristics of mature cells

2.Totipotent/unipotent progenitors

These are committed progenitor cells and have already committed to what they will become when they generate mature cells.

Question 6

What type of disease is leukaemia ?

Answer 6

It is a clonal disease-
All the malignant cells derive from a single mutant stem cell

There is a genetic alteration in one of the stem cells or progenitors.

Can cause overexpression of certain transcription factors.

The cells can permanently divide and will be continuously active.

Question 7

Outline what happens to give rise to a leukaemia stem cell

Answer 7

There is a mutation in a haematopoietic stem cell which leads to continuous self renewal and through clonal evolution , this gives rise to leukemic cells. They will permanently divide.

The oncogenic transcription factors will drive the progenitors/haematopoietic stem cells to a pre-leukemic stage through an arrest in differentiation and acquisition in cell renewal properties. The second mutation will then form leukaemia through self renewal and survival proliferation

Question 8

Outline the incidence of leukaemia

Answer 8

Leukaemia is most common in people who are aged 75 and older .
Peak rate (85-89) years old

Question 9

Describe the presentation of leukaemia ?

Answer 9

Varies between types of leukaemia

Typically first presents with symptoms due to loss of normal blood cell production :

• Abnormal bruising-commonest (due to abnormal production of platelets )
• Repeating abnormal infection (absence of white blood cells )

-Sometimes anaemia
(reduced production of RBC)

Question 10

What causes anaemia in Leukaemia ?

Answer 10

Reduced production of RBC
In the bone marrow , three lineages of cells are formed:
WBC, RBC and platelets
However in Leukaemia there will not be production of these cells.

Fatigue
Loss of Immune power
Fever
Dizziness

Question 11

How can we diagnose Leukaemia ?

Answer 11

1.When a biopsy is extracted from bone marrow .
Taken from pelvic bone and results compared with PB

Peripheral blood blasts tests (PB)
To check for presence of blasts and cytopenia
>30% blasts are suspected of acute leukaemia

Lumbar puncture- To determine if the leukaemia has spread to the cerebral spinal fluid

Question 12

What are the ways in which we can categorise Leukaemia ?

Answer 12

Cytomorphology
Immunophenotyping 
Next generation sequencing 
Fluorescence in situ  (FISH) Hybridisation  
Flow cytometry

Question 13

What is the cause of Leukamia ?

Answer 13

Not usually hereditary
Usually somatic genetic alterations

Some rare genetic diseases may predispose to leukaemia :
Fanconi’s anaemia , Downs syndrome

Question 14

What are the genetic risk factors of Leukaemia ?

Answer 14

Gene mutations involving oncogenes (activation ) or tumour suppressors (inactivation)

-Involving genes common to other malignancies (TP53-Li-Fraumeni syndrome, NF1-Neurofibromatosis) or specific to leukaemia

Chromosome aberrations:

• Translocations (BCR-ABL in CML) -95% of chronic myeloid leukaemia
• Numerical disorders (trisomy 21)

Inherited immune system problems:

• Ataxia telangiectasia
• Wiskott-Aldrich syndrome

Question 15

What are some environmental risk factors ?

Answer 15

Radiation exposure :

• Acute radiation accidents
• Atomic bomb survivors

Exposure to chemicals and chemotherapy

• Cancer chemotherapy with alkylating agents
• Industrial exposure to benzene

Immune system suppression
-Organ transplant

Question 16

What are some lifestyle related risk factors ?

Answer 16

Adult cancers :
Smoking 
Drinking 
Excessive sun exposure 
Overweight

Question 17

What are some possible childhood leukaemia causes ?

Answer 17

• Exposure to electromagnetic fields
• Nuclear power stations
• Infections during early life
• Parents smoking history
• Foetal exposure to hormones
• Mothers age when child is born

Question 18

What is the classification of Leukaemia ?

Answer 18

There are four types:

• Acute Lymphoid/Lymphoblastic leukaemia
• Chronic Lymphocytic leukaemia
• Acute Myeloid/Myeloblastic leukaemia
• Chronic Myeloid/Granulocytic leukaemia

Question 19

What does acute leukaemia mean?

Answer 19

Acute means a rapid onset and short but severe course
-Undifferentiated leukaemia
Characterised by uncontrolled clonal and accumulation of immature white blood cells (-blast )

Blast are immature cells e.g Myeloblast /Lymphoblast

Question 20

Outline what chronic leukaemia is ?

Answer 20

This is a disease which persists over a long time

Chronic leukaemia :
Differentiated leukaemia
Characterised by uncontrolled clonal and accumulation of mature white blood cells ( -cyte )

Cytes are cells which have differentiated

Question 21

What are the main differences between acute and chronic ?

Answer 21

Age :
Acute -Children / Chronic-Middle aged

Onset :
Acute -Sudden / chronic -Insidious

Duration:
Acute -Weeks/month / chronic -years

WBC counts :
Acute -variable / chronic -high

Question 22

How is acute leukaemia characterised ?

Answer 22

It is characterised by a large number of lymphoblast’s aor myeloid blasts in bone marrow and blood-undifferentiated leukaemia

High number of blasts

Question 23

What causes an increase in blast cells in Acute Leukaemia ?

Answer 23

Normally the process is :
Cell proliferation - Blast cell pool-Mature cells -Cell death (Apoptosis /Necrosis )

In acute leukaemia
Cell proliferation -Blast cell pool - (Maturation arrest )
Some cells will die before maturing

Question 24

What are the typical symptoms of acute leukaemia ?

Answer 24

The typical symptoms are due to bone marrow suppression :
Thrombocytopenia :purpura (bruising), epistaxia (nose bleed ), bleeding from gums

Neutropenia : Recurrent infections , fever

Anaemia :Lassitude , weakness , tiredness , shortness of breath

Might take a bone marrow biopsy to confirm

Question 25

Describe Acute lymphoblastic leuamiea and its presentation within the population

Answer 25

Prevalence : Commonest cancer of childhood

Origin: Cancer of immature lymphocytes

Classification: B-cell and T cell leukaemia

Treatment : Chemotherapy -Long term side effects are rare

Outcome : 5 year event free survival.

1/10 patients relapse
50% remission in 50% after chemotherapy treatment

Question 26

Describe Acute Meyloblastic Leukaemia and its presentation within the population

Answer 26

prevalence : 70 children aged under 16 diagnosed every year

origin : Cancer of immature myeloid WBC

Classification L ABsed on FAB system
(M0-M7)

Treatment : Chemotherapy , monoclonal antibodies (immunotherapy), allogenic bone marrow transplant.

Outcome -5 year event free survival (50-60%)

More bleeding and in order to distingusih the difference - blast

Question 27

How is chronic leukaemia characterised ?

Answer 27

An increase number of differentiated cells .

Affects cells with lower potency

Question 28

Outline Chronic Lymphocytic Leukaemia

Answer 28

Prevalence :3800 new cases every year -Average age =70

Origin : Large numbers of mature lymphocytes in bone marrow +peripheral blood

Symptoms : Recurrent infections :Neutropenia , suppresion of normal lymphocyet function, anamia, thrombocytopenia,lymphnode enlargement, hepatosplenomegaly( swelling and enlargement of the liver and spleen)

Treatment : Regular chemotherapy to reduce cell numbers

Outcome : 5 year event free survival of 83%

Question 29

Outline Myeloid/granulocytic leukaemia

Answer 29

Prevalence : 742 new cases diagnosed

Origin : Large numbers of mature myeloid WBC

Symptoms : Often asymptomatic and discovered through routine blood tests

Diagnosis : high white cell count -Neutrophilia in blood and bone marrow -presence of Philadelphia chromosome

Treatment :targeted therapy -Imatinib

Question 30

What is the BCR-ABL oncogene ?

Answer 30

This is the oncogene found through translocation within a small chromosome called Philadelphia chromosome

BCR-Encodes a protein that needs to be continuously active

ABL-Encodes a protein tyrosine kinase whose activity is tightly regulated (auto-inhibition)

BCR-ABLE protein has constitutive (unregulated)protein kinase activity as the ABL is now under regulation of the BCR promoter.

Question 31

Outline the consequences of unregulated tyrosine kinase activity due to BCR-ABL

Answer 31

Proliferation of progenitor cells in the absence of growth factors

Decreased apoptosis

Decreased adhesion to bone marrow stroma

Question 32

What are the applications of the BCR-ABL oncogene ?

Answer 32

95% of cases of CML have a detectable Philadelphia chromosome

Detection of minimal residual disease

Therapy: Drugs that specifically inhibit BCR-ABLE e.g. Imatinib
Cases negative for BCR-ABL will require different therapy

Question 33

What is Imatinib ?

REVISIT

Answer 33

This is a small molecule inhibitor that targets specifically ABl-CML treatment

Remission induced in more patients with greater durability and fewer side effects

Some patients become drug resistant

Abl gene is a tyrosine kinase and contributes ATP.
Competes with ATP therefore the fusion protein wont be able to phosphorylate the substrates.