Leukaemia Flashcards
What was the incidence of leukaemia in 2010?
8,257 new cases (4816 male, 3441 female)
Since the 1970s has the mortality rate of leukaemia been increasing or decreasing?
The mortality rate is decreasing, consequently the prevalence is increasing.
Which two types of chromosomal translocation cause leukaemia?
- Placing a strong regulatory element upstream of an oncogene, causing its over-expression.
- An inframe fusion event that creates a novel and/or dysfunctional protein.
What are the main symptoms of AML?
Bruising
Bleeding gums
Shortness of breath
What is the treatment for AML?
Chemotherapy
What is AML?
Accumulation of immune myeloid cells (blasts), proliferating in bone marrow.
Give 3 commonly mutated genes in AML.
CD117/c-kit
Runx1
CD135/FLT3
Give 4 common chromosomal abnormalities in AML.
t(8;21) - Runx1 (AML1-ETO fusion protein)
Inv16 - Core binding factor β subunit
t(15;17) - Retinoic acid receptor α subunit
t(9;11) - MLLT3-MLL
What is Runx1?
A transcription factor
What does Runx1 form a complex with?
Core binding factor.
Which protein causes DNA binding of Runx1 to increase 10-fold?
CBFβ
What does AML1-ETO impede?
Myeloid differentiation.
What is the most common paediatric malignancy?
ALL
What is the peak age range for ALL?
2-5 years old
What is the treatment for ALL?
Chemotherapy, radiotherapy, stem cell transplant
What percentage of paediatric patients are cured (5 year survival)?
Approximately 95%
What fraction of adult cases show post-5 survival?
1/3
What are common chromosomal translocations in ALL?
t(8;14)
t(9;22)
t(1;19)
t(12;21)
What is the most common chromosomal translocation in ALL?
T(12;21) TEL-AML1 ( >25%)
Which virus could cause overproduction of myc in ALL?
Epstein Barr Virus
What happens in t(8;14) translocation?
Myc moves to regulatory element of Eμ, this drives over-expressions expression of myc.
Which translocation is the Philadelphia chromosome?
t(9;22)
Which fusion protein does t(9;22) give rise to?
bcr/abl
What does bcr/abl create?
A novel protein tyrosine kinase (PTK)
Which pathway is the abl PTK linked to?
ras/MAP kinase pathway
What does the ras/MAP kinase pathway regulate?
Cell proliferation
Which kinase family is abl a member of?
Src
The TEL-AML1 fusion protein’s pattern of interaction with transcriptional modifiers is dramatically altered. What does this change?
The spectrum of genes targetted and expressed.
Which ALL translocation occurs in utero?
t(12;21)
What are the TEL and AML genes transcriptional regulators for?
Haematopoeisis
What needs to occur for a child with a TEL/AML translocation to develop leukaemia?
The second normal TEL gene is lost.
Which environmental factors lead to loss of TEL?
Viruses, radiation, immunodeficiency, chemicals
What is the most common geriatric malignancy in the West?
Chronic Lymphocytic Leukaemia (CLL)
Which cells are affected in CLL?
BcR+
Name 4 commonly mutated genes in CLL.
Notch1
p53
MyD88
ATM
How can CLL be treated?
Incurable, younger patients can get stem cell transplants.
What are the two forms of CLL?
Indolent - patients don’t know they have it.
Aggressive - poor 5 year survival.
What effect does IgVH status have on CLL prognosis?
Unmutated VH genes (>98% identity with germline sequence) are at elevated risk of poor prognosis.
Mutated VH genes have better prognosis.
What is Zap-70 and how does it affect CLL prognosis?
A tyrosine kinase normally associated with TcR.
High level of Zap-70 correlates with CLL progression and a poor outcome.
What plasma concentration of sCD23 suggests poor prognosis for CLL patients?
> 60ng/ml
How do telomeres affect CLL prognosis?
Shortened telomeres - poor prognosis.
Telomeres are a very good indicator of prognosis
