acute leukaemia Flashcards
what is acute leukaemia
A neoplastic condition characterized by
* Rapid onset
* Early death if untreated
* Immature cells (blast cells)
* Bone marrow failure – blast cell replace normal haematopoeitic tissue:
- Anaemia: fatigue, pallor, breathlessness
- Neutropenia: infections
- Thrombocytopenia: bleeding
Summarise haematopoietic stem cell lineage
Highlight the cell that gives rise to the leukaemia clone
AML – occur in pluripotent stem cell, multipotent, of committed to granulocyte-monocyte lineage
B-ALL - cell committed to B lineage
T-ALL - cell committed to T lineage
CLL – later cell in B lineage
leukaemia in pluripotent stem cell means -> lymphoid and myeloid cell as part of leukaemia - mixed phenotype acute leukaemia
CML - philidelphia +ve and BCRable +ve condition - possible for lymphoid differation and lymphoblastic transformation
Describe this picture
Dominant blast cell
Top – delicate granules = myeloid
Bottom – no granules, smaller blast cells, denser - lymphoid
epidemiology of AML
increase with age
Px worse with age - due to type of leukaemia and frailty
40% of adults cured
principles of chr abnormalities in AML
aberration in count or structure
these are recurrent and -> involved in development of leukamia
Molecular change – chr look ok, but when analysed for DNA then the mutation is found
- duplication
- loss
- translocation (Reciprocal translocation – if one moves back in the opposite direction)
- inversion - 2 breaks and it flips over and joins
- deletion of part of a chr
translocation in acute promyelocytic leukaemia
chr 15 and 17
abnormal 15 gets longer - extra band
17 - shorter
Abnormal is called the ‘derivitive’ takes name from centromere
translocation in acute promyelocytic leukaemia
chr 15 and 17
abnormal 15 gets longer - extra band
17 - shorter
Abnormal is called the ‘derivitive’ takes name from centromere
example of chr inversion
Difficult to recognise – confirm with molecular analysis
effect of translocations and inversions in leukaemia
Altered DNA sequence
* creation of new fusion genes (AML and ALL)
* abnormal regulation of genes (mainly ALL) – gene under influence of promotor/enhancer of another gene
chr duplication in leukaemia
Common in AML
Disease hotspots
* +8 is common (trisomy 8)
* +21 gives predisposition - both neonatal and acute megakaryoblastic leukaemia in young children
Possible dosage affect - extra copies of proto-oncogenes
definition of oncogene
gene that contribute tio causing neoblastic condition
definition of proto-oncogene
potential to develop into oncogene
chr loss or deletion in leukaemia
Common in AML
Disease hotspots - deletions and loss of **5/5q & 7/7q** (long arms)
Possible loss of tumour suppressor genes
Alternative explanation ‒ one copy of an allele may be insufficient for normal haemopoiesis
Possible loss of DNA repair systems
Type of molecular abnormalities with apparently normal chromosomes
point mutation
loss of tumour suppressor genes
partial duplication
cryptic deletion
depict normal granulocyte maturation
Myeloblast on L
Neutrophil on R
maturation of granulocytes in leukaemia
Block between myeloblast and promyelocyte
Continuing prolif
= increased myeloblast
Some forms get more developed cells
leukaemogenesis in AML
Multiple genetic hits - at least 2 interacting molecular defect synergise to give leukaemic phenotype:
Type 1 abnormalities
* promote proliferation & survival
Type 2 abnormalities
* block differentiation (which would normally be followed by apoptosis)
* * Transcription factors bind DNA - alter structure -> differentiation. If TF is disrupted -> cells cant differentiate
* in normal granulopoeisis cells -> mature neutrophils -> apoptosis
* here cells not dying and are replacing normal cells.
t(8,21) leukaemia
Failure of adequate diff – but not a complete block
good px
inv(16) t(16,16) leukaemia
blocking differentiation
eosinophilic diff - immature eosinophil haev dark purple granules
good px
inv(16) t(16,16) leukaemia
blocking differentiation
eosinophilic diff - immature eosinophil haev dark purple granules
good px
genetics of t(15,17) leukaemia
Fusion gene between these genes
Either in metaphase or interphase cell
Either see via cytogenetic analysis or FISH
Fish good because fast
Where in cell maturation pathway does t(15,17) effect
myeloblasts diff into abnormal promyelocytes
abnormal rods in cytoplasm (auer rods by fusion of granules)
slide of t(15,17) leukaemia - classic
Auer rods
giant granules
slide of t(15,17) leukaemia - variant
Granules are more delicate –less bright
Harder to dx – want FISH to confirm it.
molecular mech is the same
how can you diff between AML and ALL
Cytological features
Cytochemistry – replaced by Immunophenotyping
top is AML - fine granules
Auer rods = AML
how can you diff between AML and ALL
Cytological features
Cytochemistry – replaced by Immunophenotyping
top is AML - fine granules
Auer rods = AML
Immunophenotyping
Ab tagged with flurescent dye
Immunocytochemistry
Positive reaction with a monoclonal antibody
Flow cytometry
express CD45 - leukocyte ag
CD34 - marker of blast cells
CD13 - myeloid marker
CD33 - myeloid marker
AML
DIC with AML
Leading to gangrene on R – uncommon because get fibrinolysis too – so more commonly get bleeding
(also get DIC with acute promyelocytic leukaemia)
AML
Hyperviscosity if WBC is very high -> retinal haemorrhages, retinal exudates
Retinal exudate – leukaemic cell infiltrating the retina
Papilloedema if infiltration around optic nerve
