leukaemia Flashcards
what is leukaemia *
cancer of the blood
means white blood - marked increase in white cell count
also a bone marrow disease - not all patients have abnormal cells in the blood - but abnormalities on bm spill into blood
describe the test Attach Soundstubes *
anticoagulated blood
centrifuged
plasma layer on top
white layer - buffy coat because off white - increasing white cell count
red layer - rbc
describe the genetics of leukaemia *
series of mutations in a single lymphoid/myeloid stem cell - or one that can give rise to both (pleuripoietic stem cells)
mutations in pleuripoietic stem cell = mixed phenotype acute leukaemia - with lymphoid and myeloid leukaemic cells
lymphoid stem cell = T B or NK leukaemias
myeloid = myeloid leukaemias
need >1 mutation - no abnormality is seen clinically with 1 mutation (can see molecularly), second mutation makes the clone more aggressive - expand at the expense of other polyclonal cells
the mutations = abnormalities in proliferation (too fast), differentiation (dont mature to end stage cells) or cell survival (live too long) = steady expansion of leukaemic clone
why is leukaemia different from different cancers
uncommon to have tumours
more often the leukaemic cells replace normal BM cells and then circulate in blood
normal haemopoietic and lymphoid stem cells circulate between tissues and the blood - therefore the concepts of invasion and metastasis dont really work because the cells normally enter surrounding tissue and spread through vessels
terminology used to describe leukaemias *
those that behave in a benign manner - called chronic - means disease goes on for a long time
those that behave in a malignant manner - acute - means if not treated the cancer is very aggressive and the patient will die in weeks or months
what is the difference between lymphoid and myeloid leukaemia *
lymphoid - B T NK lineage
myeloid - any combination or granulocytic, monocytic, erythroid or megakaryocytic or multiple lineages
what are the 4 classifications of leukaemia *
acute lymphoblastic leukaemia
acute myeloid leukaemia
chronic lymphocytic leukaemia
chronic myeloid leukaemia
why do people get leukaemia *
series of mutations in a single stem cell
some mutations are from identifyable, or unidentifyable oncogenic influences - environmental
others are chance events that happen through life and accumulate in individual cells
what are the important leukaemogenic mutations *
in proto-onchogene
creation of novel gene - chimaeric or fusion gene - translocation between chromosomes - have 5’ part of 1 gene and 3’ part of another
dysregulation of a gene when translocation brings it under the influence of promoter or enhancer of another gene - turned on innappropriately
loss of function of tumour suppressor gene - from deletion or mutation - leukaemia becomes more acute
genetic tendancy to increased chromosomal breaks - likelyhood of leukaemia is increased
if cell cant repair DNA normally - error might persist but in a normal person this would be repaired - this is an inherited condition
down’s syndrome can contribute
causes of leukaemogenic mutations *
irradiation
anti-cancer drugs - cause mutations
cigarette smoking
chemicals - benzene
where are the mutations in leukaemia *
somatic cells
mutations in germ might bring favourable, neutral or unfavourable characteristics to the species
somatic may be beneficial, neutral or harmful - harmful eg leukaemia
beneficial when a mutation leads to return to normal phenotype in a cell with an inherited abnormality eg an immune deficiency or bm failure system
describe acute ML *
cells continue to proliferate but dont mature
there is a build up of immature blast cells - myeloblasts or blast cells in bm with spread into the blood
there is a failure of production of normal functionining end cells - neutrophils, monocytes and erythrocytes, platelets because bm is been taken over by immature cells
also platelets are used up in DIC which is associated with 1 type of AML
genetics of AML *
mutations affect TF - so transcription of mutiple genes is affected
the product of an onchogene prevents the normal function of the protein coded by its normal homologue
cell behaviour disturbed
describe CML *
mutations affect a gene encoding a protein signalling pathway between a cell surface receptor and the nucleus
protein encoded may be a membrane receptor or cytoplasmic protein - therefore effect of cell behaviour not as profound
but mutation may activate the cell - cell becomes independant of external signals, alterations in reactiosn with the stroma and there is reduced apoptosis so that the cells survive longer and leukaemic clone expands progressively
there is increased production of end cells
what is the difference between acute and chronic lymphoid leukaemia *
acute lymphoplastic leukaemia - increase in immature cells (lymphoblasts) with a failure of these to develop into mature T and B cells
in chronic lymphoid leukaemias, the leukaemic cells are mature, although abnormal T, B and NK cells
how does leukaemia cause, and what are the disease characteristics *
accumulation of abnormal cells leads to:
- leukocytosis
- bone pain - if acute leukaemia - rapid proliferation of cells in bone, common in children with ALL
- splenomegaly - cells move into liver
- hepatomegaly - cells move into the liver
- lymphadenopathy - if lymphoid (less common in AML - cells follow characteristic of normal myeloid cells)
- thymic enlargement - if T lymphoid
- skin inflitration - papillar lesions, thickening of the skin (leukaemis cutis)
describe the metabolic effects of leukaemia *
because of increased proliferation
increased DNA breakdown from dying leukemic cells = hyperuricaemia leads to renal failure because of deposition of uric acid in the kidney, weight loss (metabolism directed to leukaemic cells) and low grade fever and increased sweating
how does leukaemia lead to, and what are the haematologic effects *
crowding out of normal cells leads to
anaemia, thrombocytopenia, neutropenia
thrombocytopenia = bruises and haemorrhages seen on skin
why would intraventricular haemorrhage occur in someone with AML *
type with DIC = low platelets because they have all been consumed
how can AML with monocytic differentiation affect the gums *
haemorrhage
swelling - infiltration by leukaemic cells - they reflect what would happen to normal cells - migrate to gums because of chemotatic stimuli
how does CML affect the immune system *
loss of normal immune func - loss of normal T and B cells
epidemiology of ALL
largely disease of children - 2-5yrs
another peak in middle/old age - genetically different - translocation between 9 and 22 - same mutation in CML but here in lymphoid stem cell = ALL
describe how epidemiology links to causes of ALL *
suggests that B lineage ALL may be from delayed exposure to a common pathogen or conversely, that early exposure to pathogen is protective - boosts the immune system
larger family = less likely to get leukaemia
new towns near cities lower incidence than on green sites
lower class protective
early social interactions protective
study suggested enterovirus infection give protection - dont know if specific virus
describe what epi suggests about leukaemias *
result from irradiation in utero
in utero exposure to certain chemicals - possibly baygon, dipyrone, epstein barr virus
rarely ALL results from exposure to mutagenic drug, usually this is AML
clinical features of ALL *
result from an accumulation of abnormal cells:
- bone pain
- hepatomegaly
- splenomegaly
- lymphadenopathy
- thymic enlargement - in T lymphoblastic leukaemia
- testicular enlargement
resulting from crowding out of normal cells
- fatigue lethary breathlessness pallor - anaemia
- fever and other features of infection - neutropenia
- bruising, petechiae, bleeding from mucosal surface - thrombocytopenia
chest x-ray of infiltrated thymus
haematological features of ALL *
leucocytosis with lymphoblasts in the blood
anaemia - normocytic, normochromic - just because of crowding out so cells produced are normal
neutropenia
thrombocytopenia
replacement of normal bone marrow cells by lymphoblasts
investigations for ALL
blood count and film
check of liver and renal function and uric acid
bone marrow aspirate
cytogenic/molecular analysis
chest x-ray
describe blood fim for someone with ALL *
lymphoblasts - large compared to lymphocytes
high nucleocytoplasmic ratio
chromatin not dense in cells - delicate condensation
no platelets
describe a normal bone marrow film *
cells normal and a mix of types
red arrow - myeloblasts
green arrow - promyelocyte - granules
myelocyte
band neutrophil
segmented neutrophil
nucleated red cell
lymphocyte
describe bone marrow of someone with ALL *
large lymphoblast
high nucleocytoplasmic ratio
low chromatin condensation
describe immunotyping for ALL *
look for CD10+ a common ALL Ag, TdT+ marker of immaturity, and on separate panal CD19+ marker of B cell
see if normal and if T or B
cells go through a detector with a laser - they pick up the ag bound to ab
describe cytogenetic and molecular genetic analysis for ALL *
useful for managing individual pt - gives idea about prognosis - determines treatment - less intense treatment if better prognosis because want to limit SE
has permitted discovery of leukaemogenic mechanisms
hyperdiploidy - more chromosomes than usual = good prognosis
reciprocal translocation between 4 and 11 poor progniosis
what are the leukaemogenic mechanisms for ALL *
formation fo a fusion gene - only 1 of the fusion genes will be leukogenic, the other will be harmless
dysregulation of a proto-onchogene by juxtaposition of it onto promotor of another gene
point mutation in a proto-onchogene
how do you detect fusion proteins
FISH - flurescent insitu hybridisation
identify genes - colour probe for each gene (red and green)
when the genes fuse get yellow flurescent signal and residual red
can use this if cytogenetic analysis doest work because cells dont go into mitosis
common mutation in T lymphocytic leukaemia *
t(10,14) teh TCL3 gene is dysregulated by its proximetry to TCRA
what is the treatment of ALL *
supportive - red cells if anaemic, platelets, AB if febrile, antifungals if long term
systemic chemo
intrathecal chemo - LP inject int CSF, or high dose drug cross the BBB - otherwise get relapse in CNS
why do you have to look at long term treatment results
people after a certain point might start dying of SE of treatment
