16. Genetics of ALL Flashcards
What type of cells accumulate in ALL?
Immature lymphoid blasts
What are the main types of ALL and how do they differ?
B-ALL - most common, early childhood, worse prognosis with increasing age. Normal trilineage haematopoiesis not preserved
T-ALL - much rarer. Normal trilineage haematopoiesis preserved
What are the symptoms of ALL?
Fever, fatigue, weight loss, bone pain, swelling, swollen lymph nodes
What is mixed lineage ALL?
Caused by rearrangements including KMT2A/MLL
> 100 partner genes for KMT2A
Most common abnormality in infants <1yr
When do KMT2A rearrangements usually occur?
In utero
What is the prognosis of mixed lineage ALL?
Poor
What sort of FISH probe is used to detect KMT2A rearrangements? Why?
Breakapart probe
Due to >100 different fusion partners
What is the most common sub-type of ALL in adults?
BCR-ABL associated ALL
25% of adult ALL, 2-4% of childhood ALL
What is the consequence of BCR-ABL in ALL?
- Constitutive ABL1 kinase activity –> deregulated proliferation, apoptosis, differentiation –> growth and survival advantage
- Treated with TKIs
What is the prognosis of BCR-ABL associated ALL?
Poor
How does BCR:ABL differ in ALL and CML?
70% of ALL patients with BCR:ABL have IKZF1 deletion as cooperative mutation – not seen in CML
Why is FISH used for KMT2A rearrangements, BCR-ABL and ETV6-RUNX1 instead of karyotyping?
Rearrangments can be cryptic so not detectable by karyotype
What abnormality is most commonly seen in childhood B-ALL?
ETV6-RUNX1 – t(12;21)
25% of childhood cases, translocation arises in utero
What is the prognosis of ETV6-RUNX1?
Good
What is the consequence of ETV6-RUNX1?
Fusion protein affects normal function of CBF (formed of RUNX1 and CBFB) - a TF that regulates normal haematopoiesis by promoting differentiation
What is high hyper diploidy?
What is the prognosis?
51-65 chromosomes
Usually gain of 4, 6, 8, 10, 14, 17, 18, X
Good
What other mutations are often seen in high hyperdiploidy ALL?
Cooperating mutations in RAS activating pathway – FLT3, KRAS, NRAS, PTPN11
What are the different sub-types of hypodiploidy?
What’s the prognosis?
Near haploidy (23-29 chromosomes)
- Very poor prognosis
Low hypodiploidy (30-39 chr)
- Very poor prognosis
High hypodiploidy (40-44 chr)
- Most common, best prognosis
What’s the most common type of IGH rearrangement in ALL?
What’s the prognosis?
t(5;14) IL3-IGH
Hypereosinophilia
Intermediate
Describe 2 rearrangements involving TCF3 and the prognosis
- t(1;19) TCF3-PBX1 is most common
Intermediate prognosis - t(17;19) TCF3-HLF
Poor prognosis
What is the consequence of iamp(21)?
What is the prognosis?
Intrachromosomal amplification of chr 21
- Gain of at least 3 copies of large region of chr 21 including RUNX1
- High risk of relapse on standard chemotherapy, improved outcome on intensive chemo
Poor prognosis
Why are paediatric B-ALL patients tested by SNP array?
Frequent deletions involving 8 genes involved in B-cell differentiation, cell cycle regulation, proliferation, cell survival etc.
Usually secondary to a primary chromosomal abnormality
Helps with prognosis - further risk stratification when combined with cytogenetic risk - use UKALL-CNA classifier
What are the 8 frequently deleted regions in paediatric B-ALL?
BTG1
IKZF1
PAX5
CDKN2A/B
RB1
EBF1
PAR1
ETV6
What types of B-ALL have a good prognosis?
High hyperdiploidy
ETV6-RUNX1 t(12;21)
What types of B-ALL have an intermediate prognosis?
t(1;19) TCF3-PBX1
t(5;14) IL3-IGH
What types of B-ALL have a poor prognosis?
KMT2A
BCR-ABL
TCF3-HLF
iAMP(21)
Hypodiploidy
What genes are associated with an inherited susceptibility to ALL?
ETV6
PAX5
What is the role of KMT2A?
Encodes a lysine histone methyltransferase
Transcriptional co-activator with key role in hematopoiesis
