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FRCPath - Cancer > Genetics of AML > Flashcards

Genetics of AML Flashcards

1
Q

What does AML stand for?

A

Acute myeloid leukaemia

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2
Q

What does AML result from?

A

Clonal expansion of myeloid progenitors (blasts) in the peripheral blood, bone marrow or other tissues

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3
Q

When is a diagnosis of AML made?

A

When at least 20% blasts are present in peripheral blood/bone marrow

OR

When an AML-related chromosomal abnormality is detected (e.g. t(8;21), t(15;17))

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4
Q

What is the median age at diagnosis for AML?

A

Mid-sixties (<15yrs for paediatric)

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5
Q

What are the main clinical symptoms of AML?

A

Typically arise through:

  1. Bone marrow failure
    - Fatigue
    - Shortness of breath
    - Easy bruising/bleeding
    - Increased risk of infection
  2. Organ failure
    - Splenomegaly
    - Tender bones
    - Gum hypertrophy

Progress rapidly and fatal in weeks/months if left untreated.

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6
Q

Is AML cause by a single genomic alternation?

A

95% of AML cases have at least one somatic alteration, but thought to be approx 12 per AML sample (incl. an average of 3 driver mutations).

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7
Q

How does the WHO classification of AML work?

A

Defines sub-groups by incorporating morphologic, immunophenotypic, genetic and clinical features.

Disease sub-classes defined by specific recurrent genetic abnormalities are prognostically relevant.

Freq of subtypes differs between paediatric and adult AML.

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8
Q

What are the 6 main AML sub-groups defined by the WHO?

A
  1. AML with recurrent genetic abnormalities of prognostic relevance
  2. AML with MDS-related changes
  3. Therapy-related myeloid neoplasms.
  4. AML, not otherwise specified (NOS)
  5. Myeloid sarcoma
  6. DS-related myeloid proliferations (e.g. TAM)
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9
Q

What are some examples of recurrent genetic abnormalities in AML with prognostic relevance?

A

t(8;21) = RUNX1-RUNX1T1
inv(16) / t(16;16) = CBFB-MYH11
APL with PML-RARA
t(9;11) = MLLT3-KMT2A

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10
Q

What makes AML be classified as AML with MDS-related changes?

A

> 20% of blasts in PB/BM

WITH (any of):
- History of MDS/MPN
- Multi-lineage dysplasia
- Complex karyotype (>2 abnorms)
- Balanced/unbalanced abnorm

WITHOUT:
- Prior cyotoxic/radiation therapy
- Recurrent genetic abnormality

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11
Q

What is therapy-related AML?

A

Prior exposure to chemotherapy.
90% have abnormal karyotype.
Genetic abnorms mirror other AML-subtypes but with worse prognosis.

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12
Q

What falls under AML NOS (not otherwise specified)?

A

Don’t fit into other category and are mainly sub-classified based on features of the leukaemia cells (lineage/maturation level), e.g:

  • AML without maturation
  • Pure erythroid leukaemia
  • Acute megakaryoblastic leukaemia
  • Acute myelomonocytic leukaemia
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13
Q

What is myeloid sarcoma?

A

AKA granulocytic sarcoma.
Tumour mass consisting of myeloid blasts occurring at other site (not BM)

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14
Q

What type of AML is associated with Down syndrome? What is transient abnormal myelopoiesis (TAM)?

A
  1. Transient abnormal myelopoiesis (TAM)
    - Occurs in ~10% of DS newborns.
    - Onset at birth/within days.
    - 70-80% spontaneously resolve within 3 months, remaining cases develop non-transient AML in 1-3yrs.
  2. DS-related myeloid leukaemia
    - DS children = 50-fold increased risk of developing AML in first 5 yrs of life
    - Usually de novo (can be post-TAM)
    - Commonly M7 subtype
    - Blast cells carry GATA1 mutations
    - If DS AML and >5yrs old with no GATA1 mutation = conventional AML
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15
Q

Which recurrent genetic abnormalities in AML are categorised as having favourable risk outcomes?

A
  1. t(8;21) RUNX1-RUNX1T1
  2. inv(16) CBFB-MYH11
  3. Mutated NPM1 without FLT3-ITD (or with FLT3-ITDlow)
  4. Biallelic mutated CEBPA
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16
Q

What is the core binding factor in the context of AML?

A

RUNX1 and CBFB proteins heterodimerise to form the core binding factor (CBF) = essential TF for normal haematopoiesis.

The fusion proteins (RUNX1T1-RUNX1 + CBFB-MYH11) allow CBF to bind to target genes BUT transcriptional activation is lost (dom neg inhibition) = arrest of differentiation + inhibition of TP53 > increased cell survival

17
Q

Provide some information on RUNX1 and AML

A
  • t(8;21)(q22;q22)
  • Involves the RUNX1T1-RUNX1 fusion
  • Accounts for ~5% of AML
  • Typically younger patients
  • 25% have KIT mutation = poorer prognosis
18
Q

Provide some information on CBFB and AML

A
  • Commonly inv(16) (rare = t(16;16))
  • Involves the CBFB:MYH11 fusion
  • Accounts for ~5-8% of AML
  • Inv(16) is subtle so can be missed on karyotype (may need FISH/RT-PCR)
  • 30% have KIT mutation = poorer prognosis
19
Q

Provide some information on t(15;17) and APML

A
  • PML-RARA fusion
  • > 90% = t(15;17)(q24.1;q21.2)
  • 10% = complex/cryptic
  • Treat: all-trans-retinoic-acid (ATRA)
20
Q

How does the PML-RARA fusion cause APML?

A

Fusion protein binds DNA and represses transcription of retinoid acid target genes but doesn’t respond to transcriptional signal induction of the genes so they remain repressed.

PML function also disrupted - usually blocks cell growth/proliferation and induces apoptosis.

Overall: inhibition of differentiation, increased cell self-renewal + decreased apoptosis of promyelocytes.

21
Q

What is ATRA?

A

All trans retinoic acid (ATRA).

Effective therapy for APML when given alongside standard chemo.

It binds the PML-RARA fusion protein, causes it to disassociate and degrade.

Promyelocytes can then undergo normal haematopoietic differentiation and apoptosis.

22
Q

What is the most common translocation in AML?

A

t(9;11) involving MLLT3:KMT2A fusion

KMT2A: histone methyltransferase - regulates gene expression through histone remodelling

KMT2A (prev MLL) has >60 fusion partners, MLLT3 is the most common

KMT2A rearrangements lead to the overexpression of HOX genes (+ MEISI cofactor), which are normally downregulated in differentiated cells

23
Q

Name some less common AML recurrent genetic abnormalities.

A

t(6;9) DEK:NUP214
Inv(3)/t(3;3) GATA2, MECOM
t(1;22) RBM15:MKL1
Mutated NPM1
Biallelic mutated CEBPA

24
Q

What is germline predisposition to AML?

A

Mutations in myeloid malignancies nearly always presumed to be somatic events BUT now thought small portion may be due to an underlying hereditary cancer predisposition syndrome.

Not typically detected as don’t usually sequence a germline sample.

Germline inheritance of mutations in TFs like CEPBA, RUNX1 and GATA2 lead to well-described AD familial predispositions to AML.

25
Q

Can you give an example of a germline predisposition to AML

A

Familial platelet disorder with propensity to AML.

Caused by LOF mutations in RUNX1.

Mutations present in germline but don’t develop leukaemia until later in life - usually due to acquiring karyotypic abnormalities in BM cells.

FRCPath - Cancer (9 decks)

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