acute myeloid leukemia Flashcards
(43 cards)
describe the clinical presentation of patients with AML (4)
(1) fatigue - decreased rbcs - decreased o2 reaching tissues
(2) increased/unexplained bleeding - decreased platelets
(3) more prone to infections - decreased wbcs (immune cells)
(4) leukostasis - increased blasts - increased blood viscocity and poor circulation
are most cases of AML idiopathic? what are some causes?
- most are idiopathic
- other causes = genetotxic stress, family history, genetic predisposition, previous blood cancer
what are the 5 testing parameters for AML? (what is needed for a diagnosis?)
(1) clinical presentation
(2) morphology
(3) immunophenotyping
(4) cytogenetics
(5) molecular studies
describe the morphology of an AML blood smear (2)
- less than 20% blasts in the peripheral blood/bone marrow is diagnostic of AML and ALL
- AML patients blast cells have auer rods where ALL pateitns don’t
what is often the first indication of AML?
morphology observed in a blood smear
what is typically done to test for AML and cell phenotype? (to confirm AML)
bone marrow studies
describe a bone marrow aspirate done to confirm AML
- use syringe to remove liquid from the bone marrow cavity
- fluid is then used to make slides for review under a microscope
- these can then be used for further ancillary tests
describe a bone marrow biopsy done to confirm AML
- large bore needle is used to remove a core of bone marrow
- sample is then examined under a microscope in thin sections to reveal bone architechture
- sample is usually taken from the iliac crest
- this tissue can then be used for further morphological and immunohistochemistry analysis
why is a sample from the iliac crest ideal?
because as you age the areas with active bone marrow decrease and are replaced with fat, but most of the axial skeleton bone marrow remains active
what is a disadvantage to bone marrow procedures?
invasive
describe immunophenotyping using flow cytometry
- cells are incubated with fluorescently tagged antibodies
- they are then passed under a laser and fluoresce if they have the antigen of interest
- this is useful for determining the proteins expressed on the leukemic cells and their lineage (to guide treatment
describe immunophenotyping using immunohistochemistry
- done on the bone marrow biopsy tissue sections
- similar to flow cytometry - cells are incubated with antibodies attached to a colorimetric endpoint detection system
- a positive result = brown on a histology slide
describe cytogenic analysis of AML tissue
- its routine to preform a karyotype on all suspected acute luekemia cases, but FISH analysis may also be done on bone marrow sample
- this type of testing provides information on the presence of translocations which are necessary for proper classification
- recall that AML has progenitor cells that are preferentially commited to the myeloid lineage but are unable to differentiate
- translocation is the likely cause of this improper pathway
what is the two-hit model?
describes the two types of mutations required to cause leukemia:
- HIT 1 = differenetiation block - requires a mutation that will block differentiation to prevent immature progenitor cells from differentiating any further
- this often involves loss of function mutations in transcription factors needed for differentiation and often stems from chromosomal translocation events
- HIT 2 = enhanced proliferations - a mutation that enhances proliferation occurs
- typically a gain of function mutation in enzymes involved in signalling pathways (that transmit signals to the nucelus telling the cell to divide)
what are the reccuring translocations associated with AML? (3)
- t(8;21)(q22;q22) - portion of chromosome 8 was translocated onto chromosome 21
- aka core binding factor rearrangement
- q = long arm of chromosome and that portion indicates the neighbourhood involved in the translocation
- inv(16) - material on chromosome 16 in inverted
- requires skilled cytogeneticist to identify
- t(15;17) - a portion of chromosome 17 was translocated onto chromosome 15
- forming the derivative chromosome 15
- aka PML-RARA rearrangement bc contains fusion sequence derrived from PML and RARA genes
in general, how do the mutations associated with AML result in AML?
impair cellular differentiation by affecting the cellular machinery that controls cell maturation
what are the common core binding factors affected by t(8;21) and inv(16) translocations?
CBFa (aka RUNX1) and CBFβ
what is the role of core binding factors in a healthy individual
when stem cells are called upon to produce more mature cells the core binding facors lead to transcription of target genes and the activation of maturation programs
describe specifically how t(8;21) leads to AML
- after the translocation event, CFBa is fused with another protein ETO (RUNX1T1) which impairs the function of both CFB proteins
- thus, the cellular machinery can no longer activate the target gene transcription and the cells remain locked in the immature phase
describe specifically how inv(16) leads to AML
after the inversion event CFBβ is fused with another protein AMMHC (MYH11) which impairs the function of cellular machinery and results in maturation arrest
describe specifically how t(15;17) leads to AML
similar manner as other mutations - results in impaired function of cellular machinery causing maturation arrest
what do the 3 mutations leading to AML represent?
a convergence point in evolution leading to the same functional outcome
the 3 mutations leading to AML arrest leukemogenesis at which phase of the two-hit model?
HIT 1 (differentiation block)
AML is stratified into 3 risk categories based on the cytogenic abnormality, what are they?
what is the 5 year survival rate and relapse rate for each?
(1) good - if have t(8;21), t(15;17) or inv(16)
- 5 year survival rate = 70%
- relapse rate = 33%
(2) intermediate - if have normal karyotype (50% of patients)
- 5 year survival rate = 48%
- relapse rate = 50%
(3) poor - complex cytogenetics
- 5 year survival rate = 15%
- relapse rate = 78%
