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Cancer Genomics > Chronic Myeloid Leukaemia > Flashcards

Chronic Myeloid Leukaemia Flashcards

1
Q

What is Chronic Myeloid Leukemia (CML)?

A

A type of myeloproliferative neoplasm with granulocyte proliferation as a major component.

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2
Q

What category of diseases does CML belong to?

A

CML belongs to the group of myeloproliferative neoplasms (MPNs).

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3
Q

What cell lineage is mainly proliferative in CML?

A

Found in all myeloid lineages and in some lymphoid cells

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4
Q

What is the primary cause of increased WCC in CML?

A

Failure of apoptosis leads to increased WCC in CML.

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5
Q

What is the hallmark characteristic of CML?

A

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

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6
Q

What is the Philadelphia chromosome?

A

An abnormal chromosome 22 resulting from t(9;22).

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7
Q

What percentage of CML patients have the BCR-ABL1 fusion gene?

A

95% of CML patients have the BCR-ABL1 fusion gene.

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8
Q

What other structural abnormalities can be found in CML?

A

In 10% of cases: Ph duplication, isochromosome 17q, trisomy 8/19, and rearrangements at MLL (11q23) or MECOM (3q26.2).

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9
Q

What is the cytogenetic techniques to detect CML at diagnosis?

A

Karyotyping detects chromosomal abnormalities in CML and FISH detects the BCR-ABL1 gene fusion

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10
Q

What is RT-PCR’s role in detecting CML?

A

RT-PCR detects BCR-ABL1 fusion at the molecular level.

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11
Q

How does the BCR-ABL1 fusion affect cellular signalling in CML?

A

Tyrosine kinase activity of BCR-ABL1 activates RAS/MAPK and JAK-STAT pathways, leading to cell proliferation and reduced response to apoptotic stimuli.

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12
Q

What is the function of BCR ?

A

The BCR dimerization domain allows protein interaction.

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13
Q

What is the function of ABL1 ?

A

The ABL1 tyrosine kinase domain activates downstream signaling.

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14
Q

What are the phases of CML?

A

Chronic phase, accelerated phase, and blast crisis.

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15
Q

Describe the chronic phase of CML.

A

Chronic phase shows high WCC (associated with hypercellular bone. Arrow and peripheral leukocytosis), enlarged spleen, and <10% blasts.

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16
Q

What percentage of blasts characterizes the chronic phase of CML?

A

Less than 10% blasts characterize the chronic phase.

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17
Q

What characterizes the accelerated phase of CML?

A

Accelerated phase shows an increase in immature blasts.

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18
Q

Describe blast crisis in CML.

A

Blast crisis is refractory and associated with poor survival. Majority present as AML, however 20-30% of cases, blasts are lymphoid

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19
Q

Typical diagnostic workup: What is the morphology review in CML diagnostic workup?

A

Morphology checks for excess mature myeloid cells.

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20
Q

Typical diagnostic workup: How is immunophenotyping by flow cytometry used in CML?

A

Defines cell lineage, maturation, and aberrancy of abnormal cells.

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21
Q

How many BCR-ABL1 isoforms are there? State transcript size

A

3: p210 x 2, p190, p230

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22
Q

What is the common size of the BCR-ABL1 protein in CML?

A

The p210 BCR-ABL1 fusion protein size.

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23
Q

What breakpoints generate the p210BCR-ABL1 fusion protein?

A

BCR exon 13 or 14 fused with ABL exon 2 generates p210 BCR-ABL1 (e13 or b2 and e14 or b3).

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24
Q

Which transcript size is associated with BCR exon 1 breakpoints?

A

BCR exon 1 breakpoint produces the p190 protein (e1 or a2).

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25
Q

How is the p230 BCR-ABL1 fusion protein generated?

A

A larger p230 protein is generated with BCR exon 19 (e19 or c3).

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26
Q

How to detect residual disease in CML?

A

RT-PCR is crucial for monitoring residual disease in CML. A rise in BCR-ABL1 transcripts can be a sign of primary resistance to TKIs or development of resistance.

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27
Q

How often should molecular monitoring be performed in CML?

A

Molecular monitoring is performed every 3 months.

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28
Q

What is the significance of monitoring BCR-ABL1 transcript levels?

A

Tracking BCR-ABL1 levels helps identify therapy resistance early.

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29
Q

How is RT-PCR used in CML monitoring?

A

RT-PCR is used to quantitate the amount of BCR-ABL1 transcript and control genes (BCR or ABL1) to generate an expressed ratio of BCR-ABL1:control.

30
Q

What is multiplex-PCR’s role in CML?

A

Multiplex-PCR allows detection of multiple transcripts in one test.

31
Q

What are treatment methods for CML?

A

The use of tyrosine kinase inhibitors (TKIs) which have an inhibitory effect by binding to ATP-site of BCR-ABL1 and prevent downstream signalling that gives rise to leukaemia transformation.

32
Q

Name common drug treaments used to treat CML.

A

Common TKIs include imatinib, dasatinib, nilotinib, and bosutinib.

33
Q

What is primary resistance in CML?

A

Primary resistance shows failure to achieve therapeutic response; lack of response.

34
Q

What is secondary resistance in CML?

A

Secondary resistance is disease reapparance after an initial response

35
Q

What type of mutations often cause TKI resistance?

A

Point mutations in ABL1 often cause TKI resistance.

36
Q

Which mutation is ponatinib effective against?

A

Ponatinib is effective against Thr315Ile mutations.

37
Q

Why might a patient switch TKIs in CML therapy?

A

Resistance mutations may require TKI change for efficacy.

38
Q

Which TKI is effective for mutations resistant to nilotinib?

A

Dasatinib treats mutations resistant to nilotinib (Tyr253His, Glu255Lys, Phe359Val).

39
Q

How is TKI efficacy monitored in CML patients?

A

Efficacy is monitored through hematologic, cytogenetic, and molecular response.

40
Q

What is kinase domain mutation analysis?

A

Kinase domain via direct sequencing detects mutations that impact TKI efficacy.

41
Q

Why is mutation analysis recommended in treatment failure?

A

Mutation analysis directs alternative TKI choices when needed.

42
Q

What are the three types of response classifications in CML monitoring?

A

Hematological, cytogenetic, and molecular responses.

43
Q

Describe hematological response monitoring in CML.

A

Hematological response indicates improvement in blood counts.

44
Q

Describe cytogenetic response monitoring in CML.

A

Cytogenetic response measures Ph chromosome reduction.

45
Q

Describe molecular response monitoring in CML.

A

Molecular response checks BCR-ABL1 transcript reduction.

46
Q

What does a major molecular response (MMR) indicate in CML?

A

Major molecular response suggests improved survival outlook.

47
Q

What is the standard interval for CML molecular monitoring?

A

Standard interval for monitoring is every 3 months.

48
Q

Why is regular monitoring important in CML treatment?

A

Regular monitoring identifies risks of treatment failure early.

49
Q

What indicates treatment failure in CML monitoring?

A

Rising BCR-ABL1 indicates potential treatment failure.

50
Q

What does undetectable disease signify in CML patients?

A

Undetectable disease means complete response with no relapse.

51
Q

When might a patient be eligible to stop TKI therapy?

A

Eligible patients may stop TKI if disease is undetectable, without relapsing.

52
Q

What does disease progression indicate in CML during or after treatment?

A

Progression suggests need for alternative treatment strategy.

53
Q

What is a relapse in CML?

A

Relapse is the reappearance of detectable disease after response.

54
Q

What is an optimal response to CML treatment?

A

Optimal response meets therapeutic goals and suppresses BCR-ABL1.

55
Q

What is a cryptic Philadelphia chromosome?

A

Cryptic Ph chromosome is undetectable by G-banded karyotyping- cytogenetics.

56
Q

How is a cryptic Philadelphia chromosome detected?

A

Detected through FISH or RT-PCR.

57
Q

What gene fusion protein is common in CML with major BCR breakpoints?

A

Major BCR breakpoints yield p210BCR-ABL1 protein in CML.

58
Q

What pathways are associated with CML proliferation?

A

RAS/MAPK and JAK-STAT pathways drive CML cell proliferation.

59
Q

Which genetic changes in CML predict poor response to TKI?

A

Ph duplication, isochromosome 17q, trisomy 8/19 predict poor response.

60
Q

What is isochromosome 17q in CML?

A

Isochromosome 17q duplication has adverse prognostic impact.

61
Q

What does trisomy 8 indicate in CML prognosis?

A

Trisomy 8 is linked to poor TKI response.

62
Q

Why are MECOM (3q26.2) abnormalities significant in CML?

A

3q26.2 rearrangement signifies high risk in CML.

63
Q

What does MLL rearrangement indicate in CML?

A

MLL rearrangement at 11q23 shows aggressive disease course.

64
Q

What is the impact of Ph duplication on prognosis?

A

Ph duplication worsens prognosis by enhancing resistance risk.

65
Q

How does ABL1 domain mutation affect TKI therapy?

A

ABL1 domain mutations interfere with TKI binding.

66
Q

How does Ph chromosome duplication influence treatment response?

A

Ph chromosome duplication predicts low TKI response rate.

67
Q

What is a typical diagnostic workup for CML?

A

Morphology-reviewed for evidence of excess of mature myeloid cells (accumulation of mature effector cells)

Immunophenotyping by flow cytometry- define lineage, maturation and immunophenotypic aberrancy of abnormal cells

Cytogenetics and molecular data- provides further subclassification of disease type and prognostic information to guide treatment strategies

68
Q

Optimal response to TKI at 3 months?

A

BCR-ABL1 is ≤10% and/or Ph+ ≤35%

69
Q

Optimal response to TKI at 6 months?

A

BCR-ABL1 is ≤1% and/or Ph+ 0%

70
Q

Optimal response to TKI at 12 months?

A

BCR-ABL1 is ≤0.1%

71
Q

What are 5 evidence of failure to TKI at any time?

A

Loss of CHR (complete haematological response), Loss of CCyR (complete cytogenetic response), confirmed loss of MMR (complete major molecular response), New Ph+ clonal cytogenetic abnormalities, ABL1 TKD mutation

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