Wk 17: Leukaemia Flashcards
How do you classify leukaemia?
- Morphology
- Immunophenotype
- Genotype
How is immunophenotyping used in leukaemia?
- B-cells have markers called CD19 + CD20
- T-cells have markers called CD7
What are the risk factors of ALL?
- Radiation, pesticides, viruses
- Inherited syndromes
- Down syndrome, fanconi anemia, bloom syndrome, ataxia telangiectasia + nijmegen breakdown syndrome
- Caucasian
What is ALL?
- Neoplasms of B cells + T cells
- Accumulation of lymphoblasts in bone marrow + peripheral blood
- Starts in bone marrow
> 25% bone marrow replaced by malignant cells
What is the difference between leukaemia + lymphoma?
- Leukaemia: bone marrow
- Lymphoma: lymph nodes
How do you investigate ALL?
- FBC: normochromic normocytic anaemia, neutropenia, thrombocytopenia + WBC raised
- Blood film: variable bast cells
- Bone marrow: hypercellular w/ >20% blasts
- Immunophenotype: markers of B-cells + t-cells
- Immunoglobulin + TCR genes
- Molecular genetics: detects cytogenetic abnormalities + mutations
What is the pathogenesis of ALL?
1st mutation: foetus (early lymphoid progenitor cells)
- Cells undergo alteration in bone marrow: lymphoblasts + prolymphocytes
2nd mutation: childhood
- Child infections + exposure
What are the genetics observed in ALL patients?
Chimeric proteins: hybrid proteins derived from 2 fused genes
What is aneuploidy? and what is considered a good prognosis and a bad prognosis?
Gain/loss of whole chromosome:
- Hyperdiploid (>50) = good
- Hypodiploid (<44) = bad
What creates fusion genes that drive oncogenesis?
Chromosomal translocation
What is used to detect chromosomal abnormalities?
Fluorescence in situ hybridisation
What is the most common fusion gene in B-ALL?
ETV6-RUNX1
- ETV6 - recruits transcriptional repressors
- RUNX1 - regulates transcription during haematopoiesis
= Transcriptional silencing of RUNX1 targets + deregulation of haematopoiesis
What is philadelphia chromosome?
- Part of chromosome 9 is transferred to chromosome 22
- BCR-ABL fusion gene
What happens when BCR + ABL fuse together?
Fusion = loss of exon 1 turns ABL into oncogene - activates Jak-Stat + MAPK
- BCR: breakpoint cluster region
- ABL1: proto oncogene
What drug is used in philadelphia positive patients?
Imatinib
What do you give to a patient who is resistant to imatinib?
Dasatinib or ponatinib
How does methotrexate help in ALL?
Blocks:
- Pyrimidine/purine biosynthetic pathway
- Proliferation of B-cells by interfering w/ DNA synthesis , repair + replication
Why is methotrexate used?
Immunosuppressant
What is given for relapsed ALL?
Rituximab
What is the MOA of rituximab?
Binds to cell-surface protein CD20 on B-cells:
- Antibody-dependent cell mediated toxicity
- Complement-mediated cell lysis
- Induction of apoptosis
What does CD19 do?
Maintain balance btw humoral, antigen induced response + tolerance induction - target for treatment
What does PD-L1 do?
Prevent tumour cells from evading immune system
What does Blinatumomab therapy target?
CD19:
- Bispecific T-cell engaging antibodies
- Binds CD3 T-cell co-receptor
- 2nd binds protein on CD19
- Bite directs T-cells to B-cells + assist T-cell activation
What is Car-T cell therapy?
- Fuses CD-19 protein to immune cell to attack malignant B-cell
- T-cells removed from patients blood
Do Car-T cell therapy only targets malignant cells and NOT normal B-cells?
No - targets both
