Acute Myeloid Leukaemia

Question 1

AML

Answer 1

Acute myeloid leukeamia
Leukaemia of the immature WBC and RBC blast cells
Survival of patients with chromosomal translocations is greater than those with deletions or complex abnormalities

~ 50% of patients with AML do not have cytogenetic abnormalities

Question 2

APL

Answer 2

Acute promyelocytic leukaemia
Granular promyleocytes - bundle of Auer rods
Normal neutrophils
T(15;17) => PML-RARA (fusion)

Question 3

APL treatment

Answer 3

Arsenic targets PML moiety -> degradation of fusion protein
Retinoids acid targets RARA moiety -> differentiation and maturation of abnormal promyelocytes into mature WBC

Question 4

Core binding factor translocations (2xchromsomal translocations affecting them)

Answer 4

CBF is a family of heterodimeric transcription factors
Three CBFa subunits:
CBFa= AML3
CBFa2 = AML1/RUNX1
CBFa3 = AML2
Only one CBFb

T(8;21) and inv(16) affect core binding factors and alter histone acetylation

Question 5

FLT3

Answer 5

Type 3 tyrosine kinase receptor
Expressed on haematopoietic progenitor cells and majority of AML blast cells
Involved in transcription, translation of regulatory genes, blockage of apoptosis and proliferation

Question 6

Nucleoplasmin (NPM1)

Answer 6

Molecular chaperone
Implicated in:
- activation of DNA repair pathway
- P53 dependent cell cycle checkpoints

Question 7

CEBPA

Answer 7

CCAAT/enhancer binding protein alpha
Transcription factor
Pivotal role in myeloid differentiation

Question 8

Isocitrate dehydrogenase

Answer 8

Redox protection
Resistance to apoptosis
Increase cell survival and growth

Question 9

Molecular targeted therapies in AML against dysregulated growth/survival signals

Answer 9

FLT3 inhibitors
Anti-angiogenesis

Question 10

Molecular targeted therapies in AML against abnormalities in chromatin structure

Answer 10

Histone deacetylase
Demethylating agents

Question 11

Molecular targeted therapies in AML against leukaemia stem cell development

Answer 11

NFkB inhibitors
Anti-CD33 monoclonal antibodies

Question 12

Signal transduction genes mutated in myeloid malignancies

Answer 12

FLT3
JAK2

Question 13

RNA regulation gene mutated in myeloid malignancies

Answer 13

SF3B1

Question 14

Transcription regulation genes mutated in myeloid malignancies

Answer 14

TP53
RUNX1

Question 15

Epigenetic regulation genes mutated in myeloid malignancies

Answer 15

IDH1/2

Question 16

Limited clinical response of _____ patients to demethylation agents

Answer 16

AML

Question 17

Drug repurposing, repositioning and rescue

Answer 17

Analyse leukaemia cells w/ NGS mutation detection
Treat cells with DNMTi or HDACi
Identify chemo resistant cells
Treat with 2nd combination therapy

Question 18

Name three chromosomal translocations in AML

Answer 18

t(15;17) PML-RARa
t(8;21) AML-ETO
inv(16) CBFb-MYH11

Question 19

FLT3 mutations

Answer 19

ITD and TKD mutations expose binding pocket
ITD+TKD- highest mortality rate

Question 20

Different mutations in the same gene can have _________ ________ on outcome. The relative mutant level can make a difference.

Answer 20

Opposing effects

Question 21

Effect of NPM mutations

Answer 21

Ribosome biogenesis
Cell-cycle progression => DNA synthesis

The following can be inhibited:
P53
IRF1
CAD
PKR
=> cell survival