14. Genetics of AML Flashcards
What type of cells proliferate in AML?
Myeloid progenators (blasts)
Diminished capacity for differentiation
How is AML diagnosed?
> 20% blasts in blood
Or if recurrent structural abnormality is identified, regardless of blast count
What are the 2 types of core-binding factor AML?
What are the translocations?
- RUNX1-RUNXT1 - t(8;21)
- CBFB-MYH11 - inv(16) or t(16;16)
How do RUNX1-RUNX1T1 and CBF-MYH11 fusions cause AML?
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
What prognosis is associated with CBF AML?
Good prognosis
What is PML-RARA associated with?
What is the translocation?
What is the prognosis?
Acute promyelocytic leukaemia (APML)
t(15;17)
GOOD prognosis with ATRA treatment
What is the effect of PML-RARA?
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
Why is PML-RARA a medical emergency?
Rapid increase of the malignant cell crowds the bone marrow resulting in very low red blood cells and platelets –> serious bleeding
What 3 recurrent types of AML have a POOR prognosis?
- DEK-NUP214 – t(6;9)
- GATA2-MECOM – inv(3) or t(3,3)
- RBM15-MKL1 – t(1;22)
What recurrent type of AML has an INTERMEDIATE prognosis?
MLLT3-KMT2A – t(9;11)
Define class 1 mutations in AML and give examples
Activate signal transduction pathways, confer proliferative advantage on haematopoietic cells
FLT3, PTPN11, kRAS, nRAS, KIT
Define class 2 mutations in AML & give examples
Affect transcription factors and block haematopoietic differentiation
RUNX1, CEBPA, KMT2A
What is the role of FLT3?
Receptor tyrosine kinase that regulates haematopoiesis
Phosphorylates many proteins involved in cell differentiation, proliferation and survival
What are the 2 types of FLT3 mutation?
What is the prognosis of each?
- Internal tandem duplications (ITDs) in exon 14 & 15 - insertions in juxtamembrane region –> overexpression
Poor prognosis
- Tyrosine kinase mutations result in constitutive kinase activation
Unclear prognosis
When are FLT3 mutations most commonly seen?
Seen in 1/3 cases
Most frequently CN-AML, but also PML-RARA, DEK-NUP214
Why is FLT3 not used for MRD?
Lost at relapse or acquired during disease progression
When are NPM1 mutations commonly seen??
1/3 of cases, mostly CN-AML
What type of mutation are seen in NPM1?
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
What is the prognosis of NPM1?
Good in the absence of FLT3 ITD mutation
What is the phenotype of AML?
Fatigue, shortness of breath, easy bruising and bleeding, increased risk of infection
Progresses rapidly & fatal within week/months if left untreated
How are sub-types of AML categorised?
By the WHO
Classification incorporates morphologic, immunophenotypic, genetic and clinical features
What two mutations are commonly seen in CN-AML?
NPM1 & FLT3-ITD
What proportion of AML has a chromosomal abnormality?
55%
What is immunophenotyping?
Uses flow cytometry to determine lineage involvement by examining expression of cell-surface and cytoplasmic markers
What molecular testing should be done in AML as standard and why?
NPM1, CEBPA, and RUNX1 - define disease categories
FLT3, TP53, ASXL1 - poor prognosis
What genes are associated with an inherited predisposition to AML?
DDX41
ETV6
RUNX1
What is the phenotype of RUNX1-related disease?
Familial Platelet Disorder with Associated Myeloid Malignancies
Prolonged bleeding, easy bruising, thrombocytopenia, predisposition to AML
