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Clinical Immunology and Haematology > Chromosomal Translocations and Leukaemia > Flashcards

Chromosomal Translocations and Leukaemia Flashcards

1
Q

What are HSC’s?

A

are multipotent primitive cells that can develop into all types of blood cells e.g. B/T lymphocytes, granulocytes and macrophages

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2
Q

Where do HSC’s emerge from?

A

AGM - Aorta-Gonad-Mesonephros

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3
Q

In what organs can you find HSC’s?

A

Foetal liver, bone marrow and umbilical cord blood

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4
Q

What is self renewal?

A

allows preservation of the stem cell for lifetime of the organisms

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5
Q

What is Quiescence?

A

tight regulation to stop superfluous proliferation or to prevent accumulation of mutations (that could cause cancer)

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6
Q

What is apoptosis?

A

cell death mechanism to eliminate excess cells or damaged cells

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7
Q

What is the role of differentiation or lineage specification?

A

to produce intermediates that ultimately yield blood and immune cells

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8
Q

What is a hallmark of leukaemogenesis?

A

Disruption of the balance of differentiation, apoptosis and self renewal e.g. decreased differentiation and apoptosis and increased self renewal.

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9
Q

What are the normal controlling factors in haematopoiesis?

A

Transcription factors present in the environment or niche which can turn genes in a cell on or off once they are bound to the receptor in the cell membrane.

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10
Q

How does the receptor turn genes on or off after transcription factors have bound?

A

Phosphorylation, ubiquitination, ATP/GTP and oxidise/reduce

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11
Q

What is the fate choice of a cell once the transcription factors have bound?

A

Proliferate/self renew
Differentiate
Death/apoptosis
Quiescence

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12
Q

What happens in leukemia?

A

There is a new constitutively active fusion protein (BCR-ABL) present which activates the signalling pathway within the cell switching on or off the wrong gene and causing over proliferation and out of control cell growth.

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13
Q

What are 4 types of Leukemia?

A

Chronic lymphocytic leukaemia (CLL)
Acute lymphocytic leukaemia (ALL)

Chronic myeloid leukaemia (CML)
Acute myeloid leukaemia (AML)

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14
Q

What is the cytology, clinical picture and prognosis of acute leukaemia?

A

Large/plastic cells

Patient is sick

grave

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15
Q

What is the cytology, clinical picture and prognosis of chronic lymphocytic leukaemia?

A

Small lymphocytes

Often incidental findings

Pretty good

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16
Q

What acute leukemia is common in children?

A

Acute lymphoblastic leukaemia (ALL)

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17
Q

What acute leukemia is common in old age?

A

Acute myeloid leukemia (AML)

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18
Q

Why did we find out the molecular basis of leukaemia quicker than that of solid tumours?

A
  • easy to obtain biopsy of blood
  • easy to do cytogenetics of blood cells compared to solid tumours
  • visible chromosomal changes are apparent in chromosome spread
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19
Q

What percentage of adult cancers and childhood cancer is leukaemia?

A

5% adults, 50% childhood

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20
Q

What does cytogenetics involve?

A

G banding patters and chromosome paint to identify any abnormalities in the genome. This is karyotyping and you can use different colours to see this more clearly

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21
Q

What is the philadelphia chromosome?

A

This is a marker for chronic myeloid leukaemia and is when part of chromosome 22 goes onto chromosome 9, and part of chromosomes 9 goes onto chromosome 22.

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22
Q

Can you diagnose someone using chromosome painting techniques? and if so which ones?

A

Yes and you could use FISH - you can see the translocation better in anaphase

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23
Q

Is DNA from one chromosome directly linked to the DNA of the other?

A

Yes

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24
Q

What do some translocations of chromosomes result in?

A

A selective advantage to the cell

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25
Q

What are cells carrying the translocation more likely to do?

A

Proliferate

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26
Q

What leukaemia’s are caused by a translocation?

A

CML, ALL and AML

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27
Q

What are 2 consequences of chromosomal translocations?

A

Generation of a fusion protein which will have a new cellular function e.g. BCR-ABL (in CML), RUX-ETO (in AML) and MLL-AF4 (in B cell ALL).

Mis-expression of a protein (its expressed in inappropriate cell types) e.g. c-MYC in Burkitts lymphoma

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28
Q

Does leukaemia develop dependent on the type of fusion protein produced - if so why?

A

Yes as the biology of each translocation is quite different which means it could be a target for new therapies.

29
Q

What are the 3 phases of Chronic Myelogenous (myeloid) Leukaemia (CML) and their symptoms/ whats happening in the body?

A

Chronic Phase - often no symptoms and less than 10% of the bone marrow are immature blast cells - would be picked up by doing a blood test for something else.

Accelerated phase - fatigue, weight loss and enlarged spleen with 10 - 30% bone marrow cells as immature blast cells.

Acute/blast phase (blast crisis) - very unwell, large spleen with more than 30% of bone marrow as immature blast cells and a block in differentiation. Also, acquisition of additional genetic/ epigenetic abnormalities.

30
Q

Chronic myeloid leukaemia and the philadelphia chromosome - what is this?

A

A translocation between chromosome 9 and 22 which can be seen in FISH

31
Q

Is the BCR-ABL fusion protein sufficient to cause CML?

A

Yes as over time other genetic events occur and the disease progresses to acute leukaemia.

32
Q

What does native c-ABL tyrosine kinase do?

A

Its located partially in the nucleus and tightly controls regulated kinase activity

33
Q

What happens to the cytoplasmic tyrosine kinase in the BCR-ABL fusion protein?

A

It is constitutively active

34
Q

What happens if cytoplasmic tyrosine kinase is constitutively active?

A

It activates signalling pathways, decreases apoptosis and gives itself a survival advantage. It also abrogates growth factor dependency.

35
Q

Fusion tyrosin kinase displays transforming activity due to their constitutive kinase activity - what happens to downstream pathways?

A

They are activated

36
Q

Can you use fusion proteins as drug targets? Is so what is an example?

A

Yes - An ABL tyrosinse kinase inhibitor was created in 1996 using the strucutre of the ATP binding site of ABL (this is called ST1571/Imatinib/Gleevec) this leads to no downstream signalling.

37
Q

What are the different types of resistance to treatment?

A

Primary/extrinsic - no response of initial treatment
Secondary/intrinsic - resistance develops after initial positive result

38
Q

What causes resistance to ABL treatments?

A

These can be caused by point mutations in ABL protein and genetic instability of cells (secondary mutations).

39
Q

Why does the BCR-ABL oncoprotien activate downstream signalling pathways?

A

To confer malignant transformations in haematopoietic cells

40
Q

What can inhibit downstream signalling of the BCR-ABL oncoprotein?

A

Selected small molecules such as ROS,

41
Q

What is MLL?

A

Mixed lineage leukaemia

42
Q

What causes MLL?

A

Translocations

43
Q

MLL - what is methyltransferase a positive regulator of?

A

Hox gene expression and methylastion of histone H3 lysine residue 4 (H3K4)

44
Q

What is a MLL?

A

Methyltransferase

45
Q

What happens if the N terminus of the MLL is fused with a C terminus of a partner?

A

Loss of H3K4 methyltransferase domain

46
Q

What MLL domain does the majority of MLL partners fuse with and what does this do?

A

DOT1L methytransferase which positively regulates transcription of methylation of H3K79

47
Q

What does MLL fusion proteins transform haematopoietic precursors into?

A

Leukaemia stem cells

48
Q

MLL-r fusion proteins - mechanism of action and cell fate decision?

A

This causes activation of transcription elongation which leads to aberrant gene expression

49
Q

What does the leukemia phenotype (either ALL or AML) depend on?

A

the partner gene MLL is fused to

50
Q

What are the two most common MML’s

A

MLL-AF9 and MLL-AF4 (translocation)

51
Q

What controls the hox gene and can be a potent oncogenic?

A

KMT2A

52
Q

What is an essential oncogenic cofactor for leukemogenesis?

A

Menin

53
Q

Are we seeing the start of menin inhibitor trials for acute leukemias?

A

Yes

54
Q

How does the menin cause leukaemia when joined with KMT2A

A

KMT2A-rearranged AML causes leukemia through the menin linking to KMT2A-r leads to an increase in HOXA9/MEIS1 which leads to leukemia

55
Q

What is KMT2A-r?

A

The rearranged malignancy causing KMT2A

56
Q

How to menin inhibitors work? What is an example of this?

A

They prevents binfing of the menin protein to KMT2A complex causing the pathway to switch off and promoting the differentiation of leukaemic immature blasts. An example of this is Ziftomenib

57
Q

what are soem menin inhibitors being tested and how do these work?

A

Hydrocymethyl and aminomethyl - four inhibitors (M-525, M-808, M-89 and M-1121) block the interations between menin and MLL-AF4, MLL-AF9 fusion proteins to reduce the expression of MEISI1 and HOXA9 genes and inhibit the proliferation of MLL-r leukemia cells

58
Q

MML-AF9 is common in what leukaemia?

A

Acute myeloid

59
Q

Is the MLL-AF9 translocation more common in adulthood or childhood?

A

Adulthood

60
Q

What diseases do MLL-AF9 give rise to in childhood?

A

lymphoid and leukemia

61
Q

Is AF9r an aggressive leukemia?

A

Yes especially in pediatric patients compared to adult patients as prognosis is less than 5 years.

62
Q

AF9 - Is it common to relapse or have resistance to therapy?

A

Yes

63
Q

What coexisting mutations might cause the aggressiveness in AF9-AML leukaemia’s?

A

Mutations in FLT3 or the RAS pathway

64
Q

When would a cell be resistant to treatment?

A

If the mutations are acquired

65
Q

When would a cell be refractory to treatment?

A

If the cells are non-responsive

66
Q

What do most therapies target?

A

Dividing cells

67
Q

Why can’t leukaemic stem cells not be targeted by drugs so the disease persists?

A

They are quiescent

68
Q

What are the main properties of leukaemic stem cells?

A

Heterogeniety regarding their phenotype
Altered pathways - increased, self renewal etc.
Unique metabolism
Bone Marrow niche - chemoprotection, helps with growth and maintenance
Intrinsic chemoresistance - avoiding treatment

Clinical Immunology and Haematology (25 decks)

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