Wk 17: Leukaemia

Question 1

How do you classify leukaemia?

Answer 1

• Morphology
• Immunophenotype
• Genotype

Question 2

How is immunophenotyping used in leukaemia?

Answer 2

• B-cells have markers called CD19 + CD20
• T-cells have markers called CD7

Question 3

What are the risk factors of ALL?

Answer 3

• Radiation, pesticides, viruses
• Inherited syndromes
• Down syndrome, fanconi anemia, bloom syndrome, ataxia telangiectasia + nijmegen breakdown syndrome
• Caucasian

Question 4

What is ALL?

Answer 4

• 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

Question 5

What is the difference between leukaemia + lymphoma?

Answer 5

• Leukaemia: bone marrow
• Lymphoma: lymph nodes

Question 6

How do you investigate ALL?

Answer 6

• 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

Question 7

What is the pathogenesis of ALL?

Answer 7

1st mutation: foetus (early lymphoid progenitor cells)

• Cells undergo alteration in bone marrow: lymphoblasts + prolymphocytes

2nd mutation: childhood

• Child infections + exposure

Question 8

What are the genetics observed in ALL patients?

Answer 8

Chimeric proteins: hybrid proteins derived from 2 fused genes

Question 9

What is aneuploidy? and what is considered a good prognosis and a bad prognosis?

Answer 9

Gain/loss of whole chromosome:

• Hyperdiploid (>50) = good
• Hypodiploid (<44) = bad

Question 10

What creates fusion genes that drive oncogenesis?

Answer 10

Chromosomal translocation

Question 11

What is used to detect chromosomal abnormalities?

Answer 11

Fluorescence in situ hybridisation

Question 12

What is the most common fusion gene in B-ALL?

Answer 12

ETV6-RUNX1

• ETV6 - recruits transcriptional repressors
• RUNX1 - regulates transcription during haematopoiesis

= Transcriptional silencing of RUNX1 targets + deregulation of haematopoiesis

Question 13

What is philadelphia chromosome?

Answer 13

• Part of chromosome 9 is transferred to chromosome 22
• BCR-ABL fusion gene

Question 14

What happens when BCR + ABL fuse together?

Answer 14

Fusion = loss of exon 1 turns ABL into oncogene - activates Jak-Stat + MAPK

• BCR: breakpoint cluster region
• ABL1: proto oncogene

Question 15

What drug is used in philadelphia positive patients?

Answer 15

Imatinib

Question 16

What do you give to a patient who is resistant to imatinib?

Answer 16

Dasatinib or ponatinib

Question 17

How does methotrexate help in ALL?

Answer 17

Blocks:

• Pyrimidine/purine biosynthetic pathway
• Proliferation of B-cells by interfering w/ DNA synthesis , repair + replication

Question 18

Why is methotrexate used?

Answer 18

Immunosuppressant

Question 19

What is given for relapsed ALL?

Answer 19

Rituximab

Question 20

What is the MOA of rituximab?

Answer 20

Binds to cell-surface protein CD20 on B-cells:

• Antibody-dependent cell mediated toxicity
• Complement-mediated cell lysis
• Induction of apoptosis

Question 21

What does CD19 do?

Answer 21

Maintain balance btw humoral, antigen induced response + tolerance induction - target for treatment

Question 22

What does PD-L1 do?

Answer 22

Prevent tumour cells from evading immune system

Question 23

What does Blinatumomab therapy target?

Answer 23

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

Question 24

What is Car-T cell therapy?

Answer 24

• Fuses CD-19 protein to immune cell to attack malignant B-cell
• T-cells removed from patients blood

Question 25

Do Car-T cell therapy only targets malignant cells and NOT normal B-cells?

Answer 25

No - targets both