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6: Cancer genetics and treatment > 14. Genetics of AML > Flashcards

14. Genetics of AML Flashcards

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Biology 101 flashcards
1
Q

What type of cells proliferate in AML?

A

Myeloid progenators (blasts)

Diminished capacity for differentiation

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2
Q

How is AML diagnosed?

A

> 20% blasts in blood

Or if recurrent structural abnormality is identified, regardless of blast count

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3
Q

What are the 2 types of core-binding factor AML?

What are the translocations?

A
  1. RUNX1-RUNXT1 - t(8;21)
  2. CBFB-MYH11 - inv(16) or t(16;16)
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4
Q

How do RUNX1-RUNX1T1 and CBF-MYH11 fusions cause AML?

A

RUNX1 and CBF1 bind together to form CBF

CBF is a TF that regulates normal haematopoiesis - promotes myeloid differentiation

RUNX1-RUNX1T1 and CBF-MYH11 fusions still allow RUNX1 and CBF1 to bind, and CBF still binds to target DNA, but transcriptional activation domain is lost - inhibits differentation

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5
Q

What prognosis is associated with CBF AML?

A

Good prognosis

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6
Q

What is PML-RARA associated with?

What is the translocation?

What is the prognosis?

A

Acute promyelocytic leukaemia (APML)

t(15;17)

GOOD prognosis with ATRA treatment

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7
Q

What is the effect of PML-RARA?

A

Causes inhibited differentiation and increased cell renewal - promyelocytes become immortal and replicate indefinitely

Like normal RARA, PML-RARA suppresses transcription of retinoic acid target genes. But does not respond to the signal to induce transcription of genes, so the genes remain repressed.

RARA also supresses PML which normally blocks cell growth/proliferation and induces apoptosis

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8
Q

Why is PML-RARA a medical emergency?

A

Rapid increase of the malignant cell crowds the bone marrow resulting in very low red blood cells and platelets –> serious bleeding

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9
Q

What 3 recurrent types of AML have a POOR prognosis?

A
  1. DEK-NUP214 – t(6;9)
  2. GATA2-MECOM – inv(3) or t(3,3)
  3. RBM15-MKL1 – t(1;22)
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10
Q

What recurrent type of AML has an INTERMEDIATE prognosis?

A

MLLT3-KMT2A – t(9;11)

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11
Q

Define class 1 mutations in AML and give examples

A

Activate signal transduction pathways, confer proliferative advantage on haematopoietic cells

FLT3, PTPN11, kRAS, nRAS, KIT

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12
Q

Define class 2 mutations in AML & give examples

A

Affect transcription factors and block haematopoietic differentiation

RUNX1, CEBPA, KMT2A

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13
Q

What is the role of FLT3?

A

Receptor tyrosine kinase that regulates haematopoiesis

Phosphorylates many proteins involved in cell differentiation, proliferation and survival

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14
Q

What are the 2 types of FLT3 mutation?

What is the prognosis of each?

A
  1. Internal tandem duplications (ITDs) in exon 14 & 15 - insertions in juxtamembrane region –> overexpression

Poor prognosis

  1. Tyrosine kinase mutations result in constitutive kinase activation

Unclear prognosis

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15
Q

When are FLT3 mutations most commonly seen?

A

Seen in 1/3 cases

Most frequently CN-AML, but also PML-RARA, DEK-NUP214

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16
Q

Why is FLT3 not used for MRD?

A

Lost at relapse or acquired during disease progression

17
Q

When are NPM1 mutations commonly seen??

A

1/3 of cases, mostly CN-AML

18
Q

What type of mutation are seen in NPM1?

A

Typically 4bp duplications/insertions in exon 12

Frameshifts results in elongated proteins with loss of nucleolar localisation domain and/or gain of a nuclear export signal resulting in an accumulation of the protein in the cytoplasm

19
Q

What is the prognosis of NPM1?

A

Good in the absence of FLT3 ITD mutation

20
Q

What is the phenotype of AML?

A

Fatigue, shortness of breath, easy bruising and bleeding, increased risk of infection

Progresses rapidly & fatal within week/months if left untreated

21
Q

How are sub-types of AML categorised?

A

By the WHO

Classification incorporates morphologic, immunophenotypic, genetic and clinical features

22
Q

What two mutations are commonly seen in CN-AML?

A

NPM1 & FLT3-ITD

23
Q

What proportion of AML has a chromosomal abnormality?

A

55%

24
Q

What is immunophenotyping?

A

Uses flow cytometry to determine lineage involvement by examining expression of cell-surface and cytoplasmic markers

25
Q

What molecular testing should be done in AML as standard and why?

A

NPM1, CEBPA, and RUNX1 - define disease categories

FLT3, TP53, ASXL1 - poor prognosis

26
Q

What genes are associated with an inherited predisposition to AML?

A

DDX41
ETV6
RUNX1

27
Q

What is the phenotype of RUNX1-related disease?

A

Familial Platelet Disorder with Associated Myeloid Malignancies

Prolonged bleeding, easy bruising, thrombocytopenia, predisposition to AML

6: Cancer genetics and treatment (21 decks)

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