ALL Flashcards
CAR-T cell link
http://science.sciencemag.org/content/359/6382/1361.long
Give some background on ALL
ALL is acute lymphoblastic leukaemia, there is excessive expansion of the lymphoblastic lineage. It has a bimodal distribution, with 2 peaks, one occurring in childhood and one occurring in the elderly
What are the clinical features of ALL?
Bone marrow infiltration: - anaemia - neutropenia - thrombocytopaenia Organ infiltration: - Splenomegaly - Enlarged lymph nodes - Bone and joint pain CNS infiltration - poor prognosis - Nuchal rigidity Peripheral nerve dysfunction
What is the aetiology of ALL?
Multiple genetic changes of different quality in same lymphoid progenitor cell to cause full leukaemia:
- inherited predisposition
- initiating lesions conferring self-renewal - ETV6-RUNX1
- Co-operating events that bring out full leukaemia - p53 deletion BCR-ABL
- Trisomy 12 carries a 40 fold risk of AML and ALL for 0-4age
What techniques are used in the diagnosis of ALL?
Morphology FISH Flow cytometry Immunophenotyping Rt-PCR
What would you expected to see on morphology for ALL?
You would see lots of immature lymphoid blast cells There would be left shift Large basophilic cytoplasm Loose chromatin High nucleus to cytoplasm ratio
What are the cytogenetic abnormalities in ALL?
t(12;21)(p13;q22) ETV6-RUNX1 t(1;19) TCF3PBX1 Hyperdiploidy Hypodiploidy t(9;22)(q34;q11.2) BCR-ABL1 t(11q23) MLL rearranged t(4;11) KMT2A rearranged
What is the prognostic outcome of the t(12;21)(p13;q22)? What is the mechanism of disease?
Good prognosis
Important cause of pediatric ALL responsible for the peak at 2-5 years
The fusion gene forms ETV6-Runx1.
RUNX1 is responsible for encoding CBFa, who’s physiological role is to bind to CBFb and recruit activaters at the HAT region to cause transcription through IL3 and BCL2. The ETV6-RUNX1 fusion gene however loses the HAT binding region, so whilst RUNX1 is able to tether to DNA it is unable to stimulate transcription. The ETV6 is also problematic in that it itself cannot bind DNA but is tehtered to it instead by RUNX1. ETV6 recruits corepressors such as Sin3 and NCoR. The ETV6RUNX1 protein therefore is able to recruit corepressors but unable to recruit activators so it leads to chromatin condensation and transcriptional regression
What is the prognosis of t(1;19)? What is the mechanism of disease?
Used to have bad prognosis but with modern treatment its now good
Translocation leads to fusion of the TCF3 and PBX1 genes which form a fusion protein that is associated with transcriptional activators with oncogenic effect
the translocation is often unbalanced so is accompanied with loss of a chromosome
Describe the prognosis of hyperdiploidy
Good prognosis relatively
the more high diploid you are the better the prognosis
If you have trisomy of 4 and 10 you have a better prognosis(4 year EFS 97%) when compared with just one trisomy (EFS 70%)
What is the prognosis for BCR-ABL1 mutations and what is the mechanism of disease?
This has a poor prognosis and is the main cause of adult B-ALL
leads to constitutively active BCR-AB1 tk due to translocation of the ABL protooncogene onto the BCR gene. Ikaros is a tf coded by IKFZ1 and it acts as a tsg - commonly disturbed in BCR-ABL1 ALL -> prolonged survival
What is the prognosis of MLL rearrangements? What is the mechanims of the disease?
Terrible prognosis
Worse in young age
t(4;11) disturbs MLL
KMT2A is a DNA methyltransferase that switches transcription off (genes such as HOX)
What is the prognsis of t(8;14)? What are the mechanisms of disease?
MYC a protooncogene is translated into the vicinity of the promotor sequence leading to aberrantly increased expression of MYC causing sequential expression of other genes -> uncontrolled cell proliferation
POOR prognosis, but uncommon
What is the prognosis of iAMP? What are the mechanisms of disease? (ref)
Terrible prognosis (5year survival 26% Moorman et al 2007) intrachromosomal amplification of chromosome 21 occurring where there are multiple copies of RUNX1
What are the cytochemistry results for ALL?
Negative for MPO, SSB and NSE
Positive for periodic acid schiff stain
