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L3 Clinical Genomics > Chronic Myeloid Leukaemia > Flashcards

Chronic Myeloid Leukaemia Flashcards

1
Q

What specific genetic abnormality is linked to CML?

A

Philadelphia chromosome

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2
Q

What is CML an example of?

A

Myeloproliferative neoplasm (MPN)

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3
Q

What diseases are classed as MPNs? (6)

A
  • Chronic myeloid leukaemia (CML)
  • Chronic neutrophilic leukaemia (CNL)
  • Polycythaemia vera (PV)
  • Essential thrombocythaemia (ET)
  • Chronic eosinophilic leukaemia (CEL)
  • Mastocytosis
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4
Q

What is CML characterised by? (3)

A
  • Fusion of the BCR gene (22q) and the ABL1 gene (9q) in 100% of cases
  • In 95% of patients fusion occurs via translocation event = Philadelphia chromosome
  • In 5% of patients fusion occurs by a more complex rearrangement
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5
Q

What is the Philadelphia chromosome?

A

Abnormal chromosome 22 containing the BCR-ABL1 fusion oncogene

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6
Q

What was the first genetic abnormality to be linked to cancer?

A

Philadelphia chromosome

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7
Q

What is the prevalence of CML?

A

1 to 2 new cases diagnosed in the UK per 100 000 per year (rare in terms of cancer)

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8
Q

What are the symptoms of CML? (5)

A
  • Weight loss
  • Night sweats
  • Fatigue
  • Anaemia
  • Splenomegaly
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9
Q

What is splenomegaly?

A

Enlarged spleen

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10
Q

How many phases does CML have?

A

3 (triphasic)

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11
Q

What are the phases of CML? (3)

A
  • Chronic phase
  • Acceleration phase
  • Blast phase
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12
Q

What is blast phase?

A

Acute phase of the disease where blast cells account for more than 20% of peripheral blood

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13
Q

What is acceleration phase?

A

Intermediate stage which is often short-lived and therefore missed due to rapid progression of the disease

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14
Q

What is the effect of BCR-ABL1 fusion on the haematopoietic pathway? (2)

A
  • Formation of BCR-ABL1 in a myeloid stem cell reprograms the cell with deregulated and increased proliferation
  • Results in leukocytosis of the granulocyte lineage
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15
Q

How are cytosis and cytopenia linked? (3)

A
  • Proliferative leukaemias such as CML result in massive cytosis of affected lineages
  • This causes bone marrow hypercellularity and inhibits the ability of other stem cells to divide and differentiate resulting in cytopenia
  • Cytopenia is also caused by genomic abnormalities which block differentiation into mature cell types
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16
Q

When else is BCR-ABL1 observed? (2)

A
  • Acute lymphoblastic leukaemia (most common in children)
  • BCR-ABL1 is diagnostic of CML if there is also evidence of abnormal proliferation of the myeloid lineages
17
Q

What is observed in the chronic phase? (3)

A
  • Cellularity of the bone marrow is increased
  • Platelet count is high
  • Leukocytosis of granulocytes
18
Q

What is observed in the acceleration phase? (2)

A
  • Can be seen in karyotype evaluation (clonal expansion and evolution - BCR-ABL1 plus evolution)
  • Blast cells start to account for between 10 and 19% of cells in peripheral blood
19
Q

What is observed in the blast phase? (4)

A
  • Blast cells account for 20% or more of cells in peripheral blood
  • Involvement of other lineages due to de-differentiation of malignant myeloid stem cells
  • Further clonal expansion and evolution resulting in granulocytes being unable to mature so blood is full of cells with impaired function
  • Persistence of chronic features (high platelets, leukocytosis)
20
Q

How is CML diagnosed? (3)

A
  • Mostly picked up by routine blood tests showing elevated wbc counts
  • Karyotype showing reciprocal translocation between chromosomes 9 and 22 (Philadelphia)
  • CML can only be diagnosed by the presence of BCR-ABL1 fusion oncogene
21
Q

How is the BCR-ABL1 fusion gene generated by translocation event? (4)

A
  • A proximal break in chromosome 9 between the centromere and ABL1
  • A distal break in chromosome 22 between BCR and the telomere
  • Exchange of the broken segments so that the ABL1 gene from 9 fuses to the BCR gene from 22 resulting in BCR-ABL1 fusion oncogene on abnormal 22 (Philadelphia chromosome)
  • Generates an abnormally long 9q and an abnormally small and pale 22
22
Q

What is a proximal break?

A

A break in the DNA that is between the centromere and the gene of interest

23
Q

Where is the BCR gene located?

A

22q

24
Q

Where is the ABL1 gene located?

A

9q

25
Q

What is a distal break?

A

A break in the DNA that is between the gene of interest and the telomere

26
Q

What is the formal nomenclature to describe the Philadelphia chromosome translocation?

A

t(9;22)(q34;q11.2)

27
Q

How is clonal evolution detected in karyotyping?

A

Multiple cells need to be analysed to detect or exclude the presence of clonal evolution and to quantify prevalence of each clone

28
Q

What is an example of an unusual rearrangement resulting in BCR-ABL1 fusion? (5)

A
  • Three way translocation
  • First 2 breaks result in fusion of ABL1 from 9 onto BCR in 22 = BCR-ABL1 oncogene
  • Break in 4q: distal part of 22q fuses onto 4 resulting in an abnormal small 4
  • 4q fuses onto 9q resulting in an abnormal long 9
  • t(4;9;22)(q21;q34;q11.2)
29
Q

How is molecular fusion of BCR and ABL1 confirmed after observation of rearrangement in karyotype? (4)

A
  • Dual fusion FISH probes
  • Probes are specific to BCR and ABL1 regions
  • A typical translocation splits each probe signal in half so half of each signal is moved to the other derivative chromosome
  • Abnormal result is 2 fusion signals (2 red and green foci)
30
Q

Why is dual fusion FISH used to detect BCR-ABL1 fusion? (3)

A
  • Reduce false positive results
  • 2 signals are expected to co-localise by chance in 1% of human interphase nuclei which is determined by the size of the probe and the nucleus volume
  • Dual fusion reduces the chance of colocalisation to 1 in 10 000
31
Q

How are patients monitored after initial diagnosis of disease load? (3)

A
  • FISH until only 1% of nuclei are abnormal
  • Then qPCR of the transcript (more sensitive method to quantify expression rather than genomic copies of the gene)
  • Called Minimal Residual Disease (MRD)
32
Q

What tools are used for detection of relapse? (3)

A
  • FISH and qPCR
  • Both capable of rapid result turnaround
  • qPCR is more sensitive and cheaper than FISH which allows frequent monitoring of patients to detect relapse early on
33
Q
A

L3 Clinical Genomics (14 decks)

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