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Year 5 Path Charis > Haem 11 - Acute leukaemia > Flashcards

Haem 11 - Acute leukaemia Flashcards

1
Q

chromosomal translocations and inversions in leukaemia

A

creation of new fusion genes (AML and ALL)

abnormal regulation of genes (mainly ALL)

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2
Q

Types of chromosomal abnormalities in AML

A

• Types of abnormalities:
o (1) Duplication (usually trisomy) – AML
 Trisomy 8 and Trisomy 21
 Dosage effect – (having 3 copies of a proto-oncogene rather than 2 may be the underlying trigger of the leukaemia

o (2) Inversion or translocations (alters the DNA sequence)
 Creation of new fusion genes – ALL and AML
• AML
o t (8; 21) - RUNX1+RUNX1T1
o 15% of AML
o Partial block – some mature cells remain

• Core Binding Factor – AML
o Inv (16), t (16; 16)  fusion gene
o 12% of AML
o Partial block – some mature ‘eosinophil-type’ cells remain

•	APML (Acute Promyelocytic Leukaemia) 
o	t (15; 17)  PML-RARA 		
o	(3) Loss and part-deletion – AML	
	Most common = del (5q) or del (7q)
•	Loss of tumour suppressor gene 
•	One copy of an allele may be insufficient for normal haemopoiesis
•	Possible loss of DNA repair systems
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3
Q

What causes leukaemogenesis in AML?

A

• Transcription factor dysregulation + chromosomal abnormalities

Transcription factor dysregulation causes an arrest in differentiation (T2 abnormality)

Transcription factor dysregulation is an important contributor to leukaemogenesis
o Not sufficient on its own to cause leukaemia (you need T1 + T2 mutations)
o More genetic hits required (e.g. chromosomal translocation, loss of genetic material, localised DNA mutations)
 Proliferation + survival encouraged
 Differentiation blocked
 Cells do not die like normal

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4
Q

Describe T1 + T2 abnormalities

A

o Type 1 Abnormalities  promote proliferation and survival

o Type 2 Abnormalities  block differentiation

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5
Q

Give 2 examples of how transcription factor dysregulation can occur in AML

A
  • t(8; 21)

* inv(16)

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6
Q

Describe how t(8;21) translocation results in block of differentiation

A

• t(8; 21)

o RUNX1 gene – chr 21 (encodes CBFa)
o RUNX1T1 gene – chr 8
o CBF - core binding factor

  • Normal version – RUNX1/CBFa + CBFb + coactivators –-> turn on the target genes
  • Translocation 8;21 fuses RUNX1 with RUNX1T1

o Forms a fusion transcription factor which drives the leukaemia ( RUNX1T1 + RUNX1 + CBFb + co-repressors)

o New TF binds co-repressors rather than co-activators  partial differentiation block
o With this particular chromosomal abnormality there is SOME MATURATION, these are not all blast cells

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7
Q

Describe how inv(16) results in block of differentiation

A

o CBF-beta to MYH11 fusion  fusion product cannot bind to the DNA sequence  partial arrest in differentiation

o Some maturation to bizarre EOSINOPHIL precursors with giant purple granules

• Preferentially blocks differentiation to eosinophils

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8
Q

What kind of abnormality are mutations affecting CBF (core binding factor)?

A

Type 2 - block differentiation

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9
Q

What is APML associated with?

A

DIC
Auer rods
Fine granules

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10
Q

What is the abnormality in APML?

A 
o	t (15; 17)  PML-RARA fusion gene 
o	Detected using FISH

 PML gene – Chr 15
 RARA gene – Chr 17

o Causes haemorrhage – exhibits DIC and hyperactive fibrinolysis
o Characterised by an excess of abnormal promyelocytes (with rod shaped inclusions  Auer rods) + fine granules

o Slightly later block in maturation than in classic AML

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11
Q

Which cells come from myeloblasts

A 
Neutrophils
Eosinophils
Basophils
Monocytes --> Macrophages
https://upload.wikimedia.org/wikipedia/commons/f/f0/Hematopoiesis_simple.svg
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12
Q

Cytochemical staining AML vs ALL

A

Cytochemical stains

Myeloperoxidase
Sudan black stain
Non-specific esterase strain

AML + ve for all
ALL -ve for all

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13
Q

What is used in immunocytochemistry?

A

monoclonal antibodies

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14
Q

iBest way to determine lymphoid from myeloid (will show antigens)

A

Immunophenotyping

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15
Q

Best way to identify mutations

A 
Cytogenetic analysis (done on all patients)
FISH (done on some patients)
Molecular genetic analysis (done on some patients)
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16
Q

Clinical features of AML

A

o Bone marrow failure (anaemia, neutropoenia/infection, thrombocytopaenia)
 RBCs  SoB, pallor, anaemia, fatigue
 WCC  infections – may be severe + life-threatening – septic shock, renal failure, DIC

• DIC is also caused by APML
 Platelets  bleeding and bruising (APML  haemorrhage as fibrinolysis upregulated)

o Local infiltration
 Splenomegaly
 Hepatomegaly
 Gum infiltration (monocytic leukaemia; i.e. APML)
 Skin, CNS or other sites (monocytic leukaemia; i.e. APML, also ALL) – i.e. cranial nerve palsies
 Lymphadenopathy (occasionally – more in lymphomas)

o Hyperviscosity if WBC is very high  retinal haemorrhages or retinal exudates, cerebral effects

17
Q

ALL versus AML (if no granules or Auer rods how do you tell?)

A

Immunophenotyping (immunocytochemistry + immunohistochemistry)

18
Q

What is aleukaemic leukaemia?

A

no blasts in the blood but there are blasts in BM – if there are no leukemic cells in the blood you need a BM aspirate

19
Q

Diagnosis of AML

A 
Blood count and film*
Bone marrow morphology*
Immunophenotyping
Cytogenetic analysis (done on all pt)
Molecular studies and FISH (done on some pt)
  • With or without cytochemistry
20
Q

Targeted molecular therapy for

o APML
o Ph +ve (CML, but also rare AML cases)
o Biologics

A

o APML = All-trans-retinoic acid (ATRA) and A2O3
o Ph +ve (CML, but also rare AML cases) = tyrosine kinase inhibitors e.g. imatinib
o Biologics = anti-CD33 antibody (myeloid) linked to cytotoxic antibody (e.g. gemtuzumab ozogamicin

21
Q

Clinical features of ALL

A

Childhood cancer

o Bone marrow failure (anaemia, thrombocytopenia, neutropoenia)

o	Local infiltration
	Lymphadenopathy (± thymic enlargement)
	Splenomegaly 
	Hepatomegaly 
	Testes, CNS (these are ‘sanctuary sites’ as chemotherapy cannot reach them easily) 
	Kidneys
	Bone (causing pain)
22
Q

Prognosis in ALL

A

o Prognosis is very dependent on cytogenetic/genetic subgroups (particularly for B-lineage)

o	GOOD Prognosis:
	Hyperdiploidy		
	t(12;21)			
	t(1;19)	
	Ph +ve; t(9; 22) – improved prognosis with TK inhibitos

o POOR Prognosis:
 t(4;11)
 Hypodiploidy

23
Q

• Leukaemogenic Mechanisms in ALL:

A 
o	Proto-oncogene dysregulation 
	Chromosomal translocation
•	Fusion genes
•	Wrong gene promoter 
•	Dysregulation by proximity to TCR or immunoglobulin heavy chain loci

o Unknown – hyperdiploidy

24
Q

diagnosis of ALL

Why does immunophenotype matter?

Why does cytogenetic/molecular genetic category matter?

A

Why does immunophenotype matter?
AML and ALL are treated very differently
T-lineage (15%) and B-lineage (85%) ALL may be treated differently

Why does cytogenetic/molecular genetic category matter?
Ph-positive need imatinib
Treatment must be tailored to the prognosis

25
Q

ALL how to manage

  • Hyperuricaemia
  • Hyperkalaemia
  • Hyperphosphatemia
  • Extreme leukocytosis
A
  • Hyperuricaemia management (hydration, urine alkalinization, allopurinol, rasburicase)
  • Hyperkalaemia management (fluids, diuretics)
  • Hyperphosphatemia management (aluminium hydroxide, calcium)
  • Extreme leukocytosis management (WBC >200 x 10^9/l) – leukaphresis
26
Q

ALL chemo duration boys vs girls

A

• Boys treated for longer because testes are a site of accumulation of lymphoblasts
o Girls = 2 years
o Boys = 3 years

27
Q

Steps in ALL chemo

A

remission induction –> consolidation + CNS therapy –> intensification –> maintenance

** Early intrathecal chemotherapy for all – Done in all patients even if initial LP is negative (6-8 treatments)

28
Q

Leukaemia symptoms in children vs adults

A

In children – bone pain, limping, pallor, bruising, organomegaly

In adults – pallor, bruising, bleeding, infection, organomegaly

• Acute promyelocytic leukaemia
is a medical emergency
• Sudden-onset bleed = APML (blood count and coagulation screen)

Year 5 Path Charis (44 decks)

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