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Molecular basis of disease > Introduction to Leukaemia > Flashcards

Introduction to Leukaemia Flashcards

1
Q

Blood cancers

A

Leukaemia
Lymhphoma
Myeloma

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2
Q

What is leukaemia?

A

a group of malignant disorders of haematopoietic stem cells characteristically associated with increased number of white blood cells in bone marrow and/or peripheral blood.

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3
Q

Blood cell lineages

A

Blood cells are divided into 3 lineages:

  • Erythrocytes
  • Cells of lymphoid lineage (B & T lymphocytes, natural killer cells involved in adaptive immune response)
  • Cell of myeloid lineage (produces rest of leukocytes involved in innate immune response & blood clotting)
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4
Q

Differentiating cells within the haematopoietic process

A

-Haematopoietic stem cells

-Progenitor cells
>undifferentiated progenitor cells (multipotent)
>committed progenitor cells (unipotent)

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5
Q

Haematopoietic Stem Cells (HSCs)

A

· Pluripotent- can give rise to cells of every blood lineage

· Self-maintaining- a stem cell can divide to produce more stem cells

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6
Q

Characteristics of Progenitor Cells

A

· Not pluripotent anymore; either multipotent or unipotent
· Can divide to produce many mature cells
· But cannot divide indefinitely
· Eventually differentiate and mature

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7
Q

Types of progenitor cells

A

Undifferentiated Progenitor Cells (multipotent)
-can’t be differentiated between each other morphologically because they don’t show characteristics of mature cells

Committed Progenitor Cells (unipotent)
-committed to a specific lineage when they generate mature cells

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8
Q

Why is leukaemia considered a ‘clonal’ disease?

A

all the malignant cells derive from a single mutant stem cell (either a mutation in the haematopoietic stem cell or a progenitor cell):

  • This mutation converts the cell into a stem cell with self-renewal ability
  • This causes a pre-leukaemia status
  • During development in the individual’s life, acquisition of another/second mutation is necessary to give rise to a full-blown leukaemia
  • This causes abnormal levels of proliferation and cell survival, producing a leukaemia state
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9
Q

How does leukaemia first present?

A

Typically, first presents with symptoms due to loss of normal blood cell production (bone marrow suppression):

· Thrombocytopenia: purpura (bruising), epistaxis (nosebleed), bleeding from gums
· Neutropenia: Recurrent infections, fever
· Anaemia: lassitude, weakness, tiredness, shortness of breath

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10
Q

Aetiology of leukaemia

A

Exact cause of leukaemia is unclear.

Combination of predisposing factors:

  • genetic risk factors
  • lifestyle-related risk factors
  • controversial risk factors
  • environmental risk factors
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11
Q

Genetic risk factors of leukaemia and heritance

A

Not usually hereditary (except for some cases of chronic lymphocytic leukaemia)

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12
Q

Genetic risk factors of leukaemia

A

Gene Mutations involving oncogenes (activation) and/or tumour suppressor genes (inactivation)
-involving genes common other malignancies (e.g. 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’s)

Inherited Immune System Problems
-e.g. Ataxia telangiectasia; Wiskott-Aldrich syndrome

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13
Q

Environmental risk factors of leukaemia

A

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

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14
Q

Life-style related risk factors of leukaemia

A

For some adult cancers:

  • Smoking
  • Drinking
  • Excessive exposure to sun
  • Overweight
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15
Q

Controversial risk factors of childhood leukaemia

A

Possible link to childhood leukaemia (not proven):

  • Exposure to electromagnetic fields
  • Infections in early life
  • Mother’s age when child is born
  • Nuclear power stations
  • Parent’s smoking history
  • Foetal exposure to hormones
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16
Q

Leukaemia classification

A

Classified according to cell lineage (lymphoid or myeloid) and degree of terminal differentiation (acute or chronic).

Lymphoid:
-Acute Lymphoid/Lymphoblastic Leukaemia (ALL)

-Chronic Lymphoid/Lymphocytic Leukaemia (CLL)

Myeloid:
-Acute Myeloid/Myeloblastic Leukaemia (AML)

-Chronic Myeloid/Granulocytic Leukaemia (CML)

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17
Q

Acute Leukaemia

A

Undifferentiated leukaemia

Characterised by uncontrolled clonal and accumulation of immature white blood cells/multipotent progenitor cells (-blast)

  • lymphoblasts (ALL) or myeloid blasts (AML) in bone marrow and blood
  • very hard to distinguish because morphology is very similar

Sudden onset and short (weeks to months) but severe course

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18
Q

Chronic Leukaemia

A
  • Differentiated leukaemia
  • Characterised by uncontrolled clonal and accumulation of mature white blood cells/unipotent progenitor cells (-cyte)
  • persists over time (years)
19
Q

Compare the characteristics of acute and chronic leukaemia

A
20
Q

What causes acute leukaemia?

A
  • Blast cell pool is arrested and cells are not able to differentiate and mature.
  • As a consequence, there is a lack of mature cells, and there is a big pool of blast cells.
  • As the balance between cell proliferation and cell death is disrupted, there will be high levels of proliferation of blast cells and a lack of mature cells, causing acute leukaemia.
21
Q

Symptoms of acute leukaemia

A

Typical symptoms of acute leukaemia are due to loss of normal blood cell production (bone marrow suppression):

· Thrombocytopenia: purpura (bruising), epistaxis (nosebleed), bleeding from gums

· Neutropenia: Recurrent infections, fever

Anaemia: lassitude, weakness, tiredness, shortness of breath

22
Q

How is acute leukaemia diagnosed?

A

Peripheral Blood Blasts Test (PB):
-to check for presence of blasts and cytopenia

-if >30% blasts, acute leukaemia suspected

Bone Marrow Biopsy Test (BM):

-taken from pelvic bone and results compared with peripheral blood

Lumbar Puncture

-to determine if the leukaemia has spread to the cerebral spinal fluid

23
Q

Acute Lymphoblastic Leukemia (ALL)

Prevalence of acute lymphoblastic leukaemia (ALL)

A

B & T cell leukaemia
-cancer of immature lymphocytes (lymphoblasts)

Commonest cancer of childhood 31%
-but overall still not very common

24
Q

Treatment of acute lymphoblastic leukaemia (ALL) and outcome

A

Chemotherapy
-rare long term side effects

Outcome:

  • 5 year event-free survival (EFS) of 87% in 2010.
  • 1 in 10 of ALL patients relapse
  • Remission in 50% after second chemotherapy treatment or bone marrow transplant
  • poorer prognosis in adults because disease presents different cell or origin and different oncogene mutations
25
Q

Acute Myeloblastic Leukaemia (AML)

Prevalence of acute myeloblastic leukaemia (AML)

A

Cancer of immature myeloid white blood cells/myeloblasts

Very rare
-70 children aged <16 y/o diagnosed in the UK every year

26
Q

Treatment of acute myeloblastic leukaemia (AML) and outcome

A

Chemotherapy
Immunotherapy (monoclonal antibodies)
+/- allogenic bone marrow transplant

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

27
Q

Chronic Lymphocytic Leukemia (CLL)

A

Large numbers of mature (clonal) lymphocytes in bone marrow and peripheral blood

28
Q

Prevalence of chronic lymphocytic leukaemia

A

3,800 new cases diagnosed in UK every year (average age of diagnosis=70)

29
Q

Symptoms of chronic lymphocytic leukaemia (CLL)

A

· Thrombocytopenia: purpura (bruising), epistaxis (nosebleed), bleeding from gums

· Neutropenia: Recurrent infections, fever

· Anaemia: lassitude, weakness, tiredness, shortness of breath

· Lymph node enlargement

· Hepatosplenomegaly

30
Q

Treatment of chronic lymphocytic leukaemia (CLL) and outcome

A

Chemotherapy

Outcome:

  • 5 year event free survival (EFS) of 83%.
  • many patients survive >12 years
31
Q

Chronic Myeloid/Granulocytic Leukaemia (CML)

A

Large numbers of mature myeloid white blood cells

32
Q

Prevalence of chronic myeloid/granulocytic leukaemia (CML)

A

742 new cases diagnosed in the UK every year (peak rate=85-89 y/o)

33
Q

Symptoms of chronic myeloid/granulocytic leukaemia (CML)

A

Often asymptomatic and discovered through routine blood tests

34
Q

Treatment of chronic myeloid/granulocytic leukaemia (CML) and outcome

A

Targeted Therapy
-Imatinib (specifically inhibits BCR-ABL)

Outcome:

  • 5 year event free survival (EFS) of 90%
  • eventually progresses to accelerated phase and then blast crisis (allogenic bone marrow transplant needed)
35
Q

Cause of 95% of chronic myeloid/granulocytic leukaemia

A

95% of cases of CML have a detectable Philadelphia chromosome (Ph’).

· This chromosome is the result of a balanced chromosomal translocation between the long arm of chromosome 9 and the long arm of chromosome 22.

36
Q

Function of BCR Gene

A

(from chromosome 22): encodes a protein that needs to be continuously active

37
Q

Function of ABL Gene

A

(from chromosome 9): encodes a protein tyrosine kinase whose activity is tightly regulated (auto-inhibition)

38
Q

Consequence of balanced chromosomal translocation between chromosome 9 and 22

A
  • The BCR and ABL genes come closer to one another, and the promoter of the BCR gene starts regulating the expression of the ABL oncogene.
  • As a consequence of the fusion between these two genes (BCR-ABL oncogene), a fusion oncoprotein is produced which is going to be upregulated.
  • The function of this oncoprotein will still belong to the ABL gene (tyrosine kinase activity), but upregulated by the promoter of the BCR gene.
39
Q

Upregulated BCR-ABL oncoprotein causes:

A

increased tyrosine kinase, which results in:

  • Proliferation of progenitor cells in the absence of growth factors
  • Decreased apoptosis
  • Decreased adhesion to bone marrow stroma
40
Q

BCR-ABL Oncogene targeted therapy

A

Imatinib (Glivec®, ST1571)

  • inhibits BCR-ABL
  • causes apoptosis of CML cells
  • remission induced in more patients, with greater durability and fewer side effects
41
Q

Mechanism of action of Imatinib

A

ABL is a tyrosine kinase which uses ATP to phosphorylate its substrate.

Imatinib is a small molecule that binds the small pocket where ATP usually binds the ABL gene and therefore acts as a competitor.

By binding to the small pocket, ATP molecules can’t bind ABL anymore, and ABL can’t phosphorylate the substrate. As a consequence, there is activation of apoptosis of CML cells.

42
Q

Disadvantage of Imatinib

A

some patients become drug resistant (need other types of treatment)

43
Q

summary

A

Molecular basis of disease (31 decks)

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