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molecular basis of disease > intro to leukaemia > Flashcards

intro to leukaemia Flashcards

1
Q

Define Haematopoiesis

A
  • process of making blood cells and platelets

- formation of blood cells

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2
Q

Define Leukaemia

A

-malignant disorders
of haematopietic stem cells characteristically associated with increase number of white cells in bone marrow or/and peripheral blood.
-clonal disease - all malignant cells derive from a single mutant stem cell, over expression of oncogenic factors.

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3
Q

What are features of Haematopoietic stem cells (HSCs)?

A
  • multipotent - 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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4
Q

What are progenitor cells?

A

progenitor cells:

  • early descendants of stem cells
  • can divide produce many mature cells
  • but cannot divide indefinitely
  • eventually differentiate and mature, cant divide indefinitely
Multipotent progenitors (undifferentiated) 
- you cant tell the difference morphologically between myleoid progenitor cells and common lymphoid progenitor cells because they do not show characteristics of mature cells but they give rise to two different cell lines.

Unipotent progenitor cells (comitted)
- already comitted to their function

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5
Q

What are symptoms of leukemia?

A

-symptoms are due to loss of normal blood cell production
1. abnormal bruising = due to abnormal platelets
2.repeating abnormal infection = due to absence of normal WBC
3. anemia:
normally RBC, platelets and WBC in blood but in leukemia this is not produced so lack of RBC can also causes
anaemia

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6
Q

How can we diagnose leukaemia?

A

peripheral blood blasts test (PB): to check for presence of blasts and cytopenia > 30% blasts are suspected of acute leukaemia.

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7
Q

What are 3 test is used to identify leukaemia?

A
  1. peripheral blood blasts test (PB): to check for presence of blasts and cytopenia > 30% blasts are suspected of acute leukaemia.
  2. bone marrow test/biopsy (BM): results compared with PB.
  3. Lumbar puncture : to determine if the leukaemia has spread to the cerebral spinal fluid.
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8
Q

What are molecular and pathophysiological characterisation tools once leukaemia has been diagnosed?

A
  • cytomorphology
    -immunophenotyping
    -NGS
    -flow cytometry
    fluorescence in situ hybridation (FISH)
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9
Q

What causes leukaemia?

A

-combination of predisposing factors:
genetic, environment, lifestyle.
-not usually hereditary
-uncertain cause

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10
Q

What are genetic risk factors for leukaemia?

A
  1. gene mutations involving oncogenes (activation) or tumour suppressor genes (inactivation)
  2. chromosome aberrations :
    - translocation (eg: BCR-ABL in CML)
    - Numerical disorders (eg: trisomy 21 -downsyndrome)
  3. inherited immune ; system problems (eg: ataxia, telangiectasia wiskott-Aldrich syndrome)
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11
Q

What are environmental risk factors?

A
  1. radiation exposure
  2. exposure to chemicals and chemotherapy
  3. immune system suppression: eg. after organ transplant
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12
Q

What are lifestyle risk factors?

A
  1. smoking and drinking
  2. excessive exposure to sun
  3. overweight
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13
Q

What are possible link to childhood leukaemia ?

A
  • exposure to electromagnetic field
  • infections early in life
  • parents smoking
  • mothers age when child born
  • foetal exposure to hormones
  • nuclear power stations
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14
Q

What are 2 classifications of leukaemia?

A
  1. lymphoid
    - acute: lymphoblastic
    - chronic :lymphocytic
  2. myeloid
    - acute : myeloblastic
    - chronic : granulocytic
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15
Q

What is acute leukaemia?

A
  • rapid onset and short but severe course
    => acute leukaemia :
    -undifferentiated
    -characterised by uncontrolled clonal and accumulation of immature white blood cells (blasts)
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16
Q

What is chronic disease?

A

-persisting over a long time
=> chronic leukaemia
- differentiated
- characterised by uncontrolled clonal and accumulation of mature white blood cells(-cyte)

17
Q

What is the difference in acute and chronic leukaemia?

A 
1. Age 
ALL = children, CLL=elderly 
2. onset
ALL = sudden 
CLL= insidious
3. duration 
ALL=weeks to months 
CLL= years
4. WBC count
ALL = variable 
CLL= high
18
Q

What is maturation arrest in leukaemia?

A
  • normal cells
    1. cell proliferation
    2. blast cell pool
    3. mature cells
    4. cell death (apoptosis)
    but in leukaemia there is no cell death = uncontrolled cell growth.
19
Q

What are typical symptoms in acute leukaemia due to?

A
  • bone marrow suppression
    => thrombocytopenia : purpura(bruising), epistaxis (nosebleed), bleeding from gums.
    => neutropenia : recurrent infections , fever
    => anemia : lassitude, weakness, tiredness.
20
Q

acute lymphoblastic leukaemia (ALL)

A 
- prevalence: 
common cause of cancer in childhood
-origin : 
cancer of immature lymphocytes 
-classification: 
B-cells and T cells leukaemia 
- treatment : 
chemotherapy. long term effects rare
-outcomes : 
5 years event free survival, all patients relapse, 50% remission after second chemotherapy.
21
Q

acute myeloblastic leukaemia (AML)

A
  • prevalence:
    -only 70 children aged < 16 yo diagnosed in the uk.
    -origin:
    cancer of immature myeloid white blood cells
    -classification:
    based on FAB system
    Treatment:
    chemotherapy , monoclonal antibodies , +/- allogenic bone marrow transplant.
    -outcomes:
    5 year event -free survival of 50-60%
22
Q

Chronic lymphocytic leukaemia (CLL)

A
  • prevalence:
    3,800 new cases diagnosed in UK every year
  • 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, anemia , thrombocytopenia, lymph node enlargement, hepatosplenomegaly.
    -treatment:
    regular chemotherapy to reduce cell numbers
    -outcomes:
    5 year event free survival (EFS) of 83%. many patients survive >12 yrs
23
Q

Chronic myeloid/granulocytic leukaemia (CML)

A

=> Prevalence
-742 new cases diagnosed in UK yearly (85 y/o)
=>origin
-large numbers of myeloid white blood cells.
=> symptoms:
- often asmptomatic and discovered through blood test
=>diagnosis:
-very high white cells count (neutrophilia) i blood and bone marrow, presence of philadelphia chromosome
=>treatment:
-targeted therapy : imatinib
=> outcome
- 5 year event free of 90%
Eventually progresses to accelerated phase and then blast crisis - allogenic bone marrow transplant.

24
Q

BCR - ABL oncogene

philadelphia

A
  • 95% of casses of CML have a detectable philadelphia chromosome
  • it is a translocation of ABL gene on chromosome 9 and BCR gene on chromosome 22.
  • the translocated chromosome 22 has BCR-ABL gene (oncogene)
25
Q

What do BCR encode for?

A

BCR: encodes a protein that needs to be continuously active

26
Q

What are consequences of BCR-ABL translocation (phelidelphia chromosome)?

A
  • BCR-ABL protein has unregulated protein tyrosine kinase activity and is continuously active.
  • Tyrosine kinases are important mediators for cell proliferation and apoptosis.
  • This leads to proliferation of progenitor cells even in the absence of growth factors.
  • decreased apoptosis
  • decreased adhesion to bone marrow stroma.
  • leads to leukaemia (WBC cancer)
27
Q

How can we use fluorescence to detect phelidelphia chromosome to get an indication of leukaemia?

A
  • fluorescent used
  • LSI ABL (9q34) = red
  • LSI BCR (22q11) = green
  • BCR-ABL gene fusion = green and red/yellow bc of overlap of colour.
28
Q

What are applications of BCR-ABL oncogenes?

A
  1. Diagnosis: 95% of cases of CML have detectable Ph’ chromosome.
  2. Detection of minimal residual disease
  3. Therapy: Drugs that specially inhibit BCR=-ABL. eg. Imatinib Cases negative for BCR-ABL require different therapy.
29
Q

How does imatinib targeted therapy work?

A
  • imatinib is a small molecule inhibitor that binds to pockets of BCR-ABL blocking ATP from binding.
  • ATP binding is needed to phosphorylate the substrate tyrokinase which prevents downstream pathways that lead t leukaemia.
  • remission induced in more patients, with greater durability and fewer side effects
  • some patients become drug resistant.
30
Q

What is the prevalence of leukemia?

A
  • found in older people

- higher in males than females

31
Q

What do ABL encode for?

A

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

molecular basis of disease (29 decks)

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