Brainscape's Knowledge GenomeTM

Browse over 1 million classes created by top students, professors, publishers, and experts.


See full index

Cytogenetics > ALL > Flashcards

ALL Flashcards

1
Q

What is ALL?

A

Acute Lymphobastic Leukaemia

Characterised by accumulation of immature lymphoid cells (blasts) in the bone marrow and in most cases the blood.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
2
Q

What are the 2 subcategories of ALL? What are they? Which is more frequent?

A

B-cell: malignancy of lymphoblasts which are committed to the b-cell lineage

T-cell: malignancy of lymphoblasts which are committed to the t-cell lineage

B-cell is most common and accounts for 85% of childhood ALL and 75% of adult ALL

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
3
Q

Who is ALL most often seen in?

A

Children

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
4
Q

What percentage of paed cancer and paed leukaemia does it account for?

A

25% of paediatric cancer

75% of paediatric leukaemia

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
5
Q

What is the quotable abnormality rate in paed and adult ALL?

A

Paediatric - 80%

Adult 70%

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
6
Q

Why are ALL samples a particular challenge for the laboratory?

A

They don’t culture very well:

  • can have low mitotic index
  • cells can have tendency for apoptosis
  • chromosome morphology is poor
  • normal cells can end up outgrowing the leukaemic clone
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
7
Q

What cultures do we set-up on a new ALL?

Why?

A

We set up 3 cultures if possible:

  • a direct culture with 45 mins of colcemid
  • 24 hour culture with 45 mins colcemid
  • 24 hour culture with either 2hrs colcemid or a dilute overnight colcemid

Increases our chances of detecting an abnormal clone

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
8
Q

Do all prognostically relevant FISH tests have to be carried out as urgent upon receipt?
What do we do with new ALLs?

A

No, the frequency of the principle translocations differ by age. Therefore tests can be carried out sequentially:

Infants: MLL/KMT2A most common
Paediatric: ETV6-RUNX1 most common
Adult: t(9;22) most common

Remainder of prognostically important rearrangements can then be tested for.

We do direct FISH on receipt though of KMT2A, ETV6-RUNX1 and BCR-ABL.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
9
Q

According to BPG hw many metaphase cells should we look at on:

  • a normal sample?
  • an abnormal sample?
A

Normal:
- 20 cells, 10 analysed and 10 checked.
If can’t get 20, minimum of 10 but must include rider on the report to state partial analysis.

Abnormal:
- ideally 10, however can report on less as long as criteria for a clone has been met.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
10
Q

When interpreting an ALL result what sources can be used?

A

WHO classification subtypes

Risk stratification can be used if patient is enrolled onto a trial

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
11
Q

Where can information about prognosis be obtained from?

A

The WHO or from international/national studies (as long as we keep in mind that some prognoses are based on the protocol used which may be different locally).

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
12
Q

Why is chromosome analysis at relapse particularly useful?

A

Identify karyotypic evolution

Indicate a new secondary malignancy

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
13
Q

What is the reporting time for a new ALL?

A

BPG state 14 working days for new diagnoses
However also states that any results that confer a poor prognosis need to be given as soon as possible

(we give them a prelim FISH within 3 calendar days which includes MLL, BCR-ABL and ETV6-RUNX1).

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
14
Q

At what age does the incidence of paediatric ALL peak?

A

2-5 years old

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
15
Q

How common are cytogenetic abnormalities in ALL?

A

Very!
Most patients will have an abnormality.
80% of children abnormal K
70% of adults abnormal K

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
16
Q

What is the cut off between paediatric and adult AML according to BPG?

A

25yrs in BPG

Varies between trials though.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
17
Q

Why are immunophenotyping investigations key in ALL?

A

B and T cells are morphologically indistinguishable.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
18
Q

What is the difference between Lymphoblastic Leukaemia and Lymphoblastic Lymphoma?

A

Disease presenting in BM or PB = leukaemia

Disease presenting primarily in nodal or extranodal (lung, skin) sites = lymphoma

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
19
Q

Name some sites that can show involvement by an ALL?

A 
CNS (brain and spinal cord)
Lymph nodes
Spleen
Liver
Testes
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
20
Q

What is the WHO classification of ALL’s?

A 
B-lymphoblastic, NOS
B-lymph with recurrent genetic abnormalities:
- t(9;22);BCR-ABL
- t(V;11q23);KMT2A rearranged
- t(12;21);ETV6-RUNX1
- with hyperdiploidy
- with hypodiploidy 
- t(5;14);IL3-IGH
- t(1;19);TCF3-PBX1

T-Lymphoblastic leukaemia/lymphoma.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
21
Q

What is the most common abnormality seen in infants with ALL?

A

Rearrangement of MLL (KMT2A) 11q23

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
22
Q

What MLL/KMT2A rearrangements are there and which is most common?

A

Most common: t(4;11)

Key event lies on the der(11) MLL-AFF1 / KMT2A-AFF1

Also: t(11;19) with MLLT1 and t(9;11) with MLLT3

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
23
Q

What prognosis is associated with ALL with a KMT2A rearrangement?
What treatment would be given?

A

Very poor regardless of partner.

Only real treatment is a bone marrow transplant.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
24
Q

What theory is there for why MLL rearrangements are so often seen in infants <1yr old?

A

May occur in utero

Have been identified in neonatal blood spots

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
25
Q

What clinical picture might you expect in an ALL with a KMT2A rearrangement?

A

Young
Very high WCC
Organomegaly
CNS involvement

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
26
Q

What is unusual about the immunophenotypic picture in ALL with KMT2A rearranged?

A

Co-expression of myeloid and lymphoid antigens.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
27
Q

Where does the key event always lie in ALL with KMT2A rearranged?

A

Always on the der(11)

The bit of MLL that moves can be lost without affecting the rearrangement (e.g. might show on FISH as deleted).

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
28
Q

What is hyperdiploidy? Who is it seen in? What symptom might you expect?

A

A clone with between 51 and 65 chromosomes

Typically seen in children, approx 25% of childhood ALL

Usually have a low WCC

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
29
Q

What particular age group would you expect a child to be if they presented with hyperdiploid ALL?

A

Between 1 and 9 yr - likely to be between 3-5 yrs.

30
Q

In childhood ALL with hyperdiploidy what chromosomes might you see gained? Do you usually only see 1 extra copy or more?

A

Typically you might see 4, 6, 10, 14, 17, 18 and X

Also see extra copy of 21 and can often be 2 extra copies of 21

31
Q

If you were to see a hyperdiploid clone with another well known rearrangement such as the t(9;22) which event would dictate the prognosis?

A

The t(9;22) would classify the ALL and dictate the prognosis (POOR)

32
Q

Are there any structural abnormalities which are seen in hyperdiploidy?

A

Sometimes see:

  • dup1q
  • del6q
  • abn 9p and 12p
33
Q

If you had a clone which contained 54 chromosomes but contained 4 copies of certain chromosomes (possibly 6, 10, 14, 18, 21, X) what could this be?

A

This could be doubling up of a ‘near haploidy’ clone to make itself look like hyperdiploidy.

34
Q

What prognosis is associated with ‘near haploidy’?
What is dangerous about near haploidy clones?
What chromosomes might give a near haploid clone away?

A

Prognosis is POOR
Might be dismissed as a broken met.
Often chromosome 3 and 7 are monosomic. These would then be disomic in a doubled up clone.

35
Q

What is the most common structural rearrangement seen in childhood ALL?
What age group is it most common in?
What percentage is it seen in?
How is it detected?

A

The t(12;21) translocation involving ETV6-RUNX1.

Typically between 3-6yrs

Seen in 25% of childhood ALL.

Detected by FISH as it is cytogenetically cryptic.

36
Q

What is the most common secondary abnormality seen alongside the t(12;21)?
How is this detected?

A

Deletion of the normal 12p - seen in ~50% by g-banding

Can be seen cytogenetically but also would be detected by our routine FISH probe.

37
Q

If you had a sample from a child and you saw a deleted 12p, what might you be concerned about?

A

That the ‘other’ chromosome was involved in a cryptic t(12;21) rearrangement - put ETV6-RUNX1 probe on to rule out.

38
Q

What is the prognosis associated with the t(12;21)(p13;q22) rearrangement?
Does it change the prognosis if the non-translocated 12p is deleted?

A

Good/favourable prognosis

No, prognosis still favourable

39
Q

What genes are involved in the t(1;19)(q23;p13) rearrangement?

A

PBX1 (1) and TCF3 (19)

40
Q

What is unusual about the t(1;19) rearrangement?

How is this thought to arise?

A

It often exists in an unbalanced for e.g. just the der(19) is present in the karyotype with 2 normal copies of chromosome 1.
Speculation is that trisomy 1 is the first hit, then t(1;19) and then loss of der(1) to return to diploid. (This would make sense as maybe in the balanced carriers it is a ‘normal’ 1 that is lost v in unbalanced carriers the der(1) is lost.)

41
Q

What is the prognosis of the t(1;19)? What is the prognosis of the unbalanced version?

A

Prognosis is intermediate, but maybe those with the unbalanced version do slightly better.

42
Q

Are there any variants of the t(1;19) rearrangement?

What is the prognosis?

A

Yes, the rare t(17;19) rearrangement which involves TCF3 (19) and HLF (17).

Has a dismal prognosis!

43
Q

What tests would we do on a failed ALL?

Why these tests?

A

FISH on arrival using BCR-ABL, MLL and ETV6-RUNX1

Attempt karyotype

If initial FISH has shown any evidence of hyperdiploidy then we would put further FISH on.

Could also use CEP3/CEP7 to rule out hypodiploid K.

If complete fail - FISH for TCF3-PBX1 and TCF3-HLF with our new probe set.

This covers all of the most significant genetic prognostic factors in paediatric and also all adult ones except the complex karyotype, according to BPG.

44
Q

What are the 4 immunophenotypic classifications of b-cell ALL?

What rearrangements are associated with which?

A

Pro-B ALL such as MLL and BCR-ABL

Common B-ALL such as 12;21 and hyperdiploidy

Pre B-ALL such as 1;19

Mature B-ALL such as 8;14

45
Q

What is the most common structural rearrangement in adult ALL?

A

t(9;22)(q34;q11)

BCR-ABL

46
Q

What secondary abnormalities might be seen in a BCR-ABL positive ALL?

A

Could be seen with hyperdiploid (in which case still poor prognosis) or complex karyotype.
Secondary abs similar to CML - +Ph, -7, del7q are most frequent.
Not usually i(17q).

47
Q

What is the prognosis of BCR-ABL in ALL?

A

POOR

48
Q

What size protein can be seen in Ph+ ALL?

A

Minor (p190) and major (p210) breakpoints are both seen in ALL.

p190 is ONLY seen in ALL and if found is evidence of de novo ALL.

The majority (90%) of Ph+ children will have the p190 protein formed when the breakpoint in BCR is minor (m).

p210 can be seen in ALL and in CML in lymphoid blast crisis - no way to know which it is really.

49
Q

What deletion has been shown to occur in Ph+ ALL?

A

IKZF1 (IKAROS) deletion (7p)

50
Q

What has improved the outlook for patients with BCR-ABL?

A

Tyrosine Kinase inhibitor therapy such as Imatinib. Has shown good results in ALL patients.

51
Q

What is iAMP21?

A

Intrachromosomal amplification of chromosome 21.

Seen mainly in children but can be seen in adults.

Defined as 5 or more copies of RUNX1, 3 or more EXTRA copies on the same chromosome.

Prognosis is POOR depending on the protocol used.

52
Q

Rearrangements involving which gene are examples of ‘position effect’ changes in ALL?
Which translocations are most common?

A

MYC rearrangements
t(8;14) is most common IGH-MYC (H=heavy)
t(2;8) involves IGK-MYC (K=kappa)
t(8;22) involves IGL-MYC (L=lambda)

53
Q

What genes are involved in the t(8;14)(q24;q32) rearrangement?
What are the variants of this translocation?
Where genes are involved in each?
Where does the key event lie?

A

MYC and IGH

t(2;8) and t(8;22) are variants and involve IGK and IGL

Key event is on 14 in the classic rearrangement. In the other 2 translocations it stays on the 8.

54
Q

What is the underlying cause of the pathogenesis of these rearrangements?

A

The overexpression of MYC due to it’s repositioning next to either IGH, IGK or IGL

55
Q

What is the main role of MYC?

A

Protein that it encodes plays a role in:

  • cell cycle progression
  • apoptosis
  • cellular transformation
56
Q

What happens when MYC moves next to one of the immunoglobulin loci?
What does it cause?

A

MYC comes under the influence of the promoter sequences and enhancer elements of a constitutively active loci e.g. IGH, IGK, IGL

= deregulation and increased transcription of MYC
= increase cell division
= proliferation in the absence of growth factors

57
Q

What is the prognosis of the t(8;14) or its variants?

A

Previously poor.

But, outlook has improved with modern chemotherapy regimes.

58
Q

How does ALL with t(8;14) or its variants typically present?

What would the immunophenotypic classification of this disease be?

A
  • known as Burkitt Leuk/Lymph
  • can be in the marrow or the lymphatic system
  • lymphatic disease can infiltrate marrow
  • CNS involvement common with bulky extramedullary disease

Classed as mature B-ALL

59
Q

What is T-cell ALL?

What percentage of ALL does it account for? More or less common than B-ALL?

A

Neoplasm of lymphoblasts which are committed to the T-cell lineage.

Much less frequent that B-ALL - approx 15%

60
Q

Are there any genetic abnormalities in T-ALL which stratify treatment?

A

No.

61
Q

What genetic abnormalities is T-ALL most commonly associated with?
Which are the main 2 chromosomes on which these lie?

A

Rearrangements of the T-cell receptor genes (TCR)

7 and 14

62
Q

What are the names of the T-cell receptor genes and what are their locations?

A

T-cell receptor:
Alpha and Delta together at 14q11
Beta is at 7q34
Gamma is at 7p14

63
Q

Which are the most common partners of the TCR genes?

A

TLX1 at 10q24

TLX3 at 5q35

64
Q

Are the rearrangements involving the T-cell receptor genes cytogenetically visible?

A

They can be, but they can also be cryptic and not visible on K.

65
Q

What are the 3 most common rearrangements that involve TCR genes?

A

t(5;14)(q35;q32) - cryptic

t(7;10)(q34;q24) and t(10;14)(q24;q11)

66
Q

If a sample came in which was query ‘mixed phenotype Acute Leukaemia’, what tests would we put on?
What prognosis is associated with these?

A

We would do an urgent direct for MLL/KMT2A and BCR-ABL

Poor prognosis.

67
Q

What update was given in September 2018 by Leukemia Research Group?

A

Screening for ABL-class fusions in patients diagnosed with ALL.

68
Q

Who are this group? Why do we follow their advice?

A

Renowned research group who have an official role within national clinical trials involving leukaemia.

Not accredited so cannot do any diagnostic work.

But can ask them for advice.

69
Q

What on particular do they recommend from Sept 2018 onwards?

Why?

A

All ALL patients, both B and T cell, if normal for the usual FISH panel, t(1;19) + var and ploidy are recommended to have FISH using probes for the ABL-like fusion genes such as PDGFRA/B and ABL1/ABL2.

These patients have been shown as having sensitivity to imatinib and disatinib, in some cases patients with refractory disease at the end of treatment have even been put into complete remission by TKI therapy.

71
Q

How might testing for ALL change in future?

A

A B-ALL patient might end up having:
ETV6-RUNX1, KMT2A, BCR-ABL then TCF3-PBX1, HLF-TCF3 then PDGFRA, PDGFRB, ABL1 and ABL2

ALOT of work- a sequencing panel may be more appropriate in future once they are more widely available.

74
Q

How would you report one of these cases?

A

These results are consistent with the presence of an ABL-class fusion gene which may indicate sensitivity to a tyrosine kinase inhibitor.

Cytogenetics (44 decks)

Brainscape helps you reach your goals faster, through stronger study habits.
© 2024 Bold Learning Solutions. Terms and Conditions