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Genetics of Adolescent/Young Genetics of Adolescent/Young Adult ALLAdult ALL
(Cytogenetics)(Cytogenetics)Christine J Harrison
Professor of Childhood Cancer Cytogenetics
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Cytogenetics Group
Clinical Trial Service Unit
Clinical Trial Coordinators
UK Cancer Cytogenetics Group
Leukaemia Research Cytogenetics Group Leukaemia Research Cytogenetics Group
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Cytogenetic subgroup by ageCytogenetic subgroup by age
0%
20%
40%
60%
80%
100%
0
1-4
5-9
10-14
15-19
20-24
25-29
30-34
35-39
40-44
45-49
50-54
55-59
Age (years)
Pro
porti
on o
f cas
es
t(4;11)/11q23 t(12;21) HeH t(9;22) t(1;19) 14q32 Other
<
Moorman 2007
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AYA by Age at Diagnosis and Treatment Trial AYA by Age at Diagnosis and Treatment Trial 19901990--present (n=1,205)present (n=1,205)
0
40
80
120
160
200
13 14 15 16 17 18 19 20 21 22 23 24
Age at diagnosis
Num
ber o
f pat
ient
s
ALL2003 (N=384) ALL97 (N=221) UKALLXI (N=108) UKALLXII (N=492)
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Age groups (n=1,205)Age groups (n=1,205)
15-19 yearsn=544, 45%
13-14 years n=432, 36%
20-24 years n=229, 19%
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Sex Ratio (1.74M:1F)Sex Ratio (1.74M:1F)
Males, 765,63%
Females, 440, 37%
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Immunophenotype (n=1,132)Immunophenotype (n=1,132)
Mature-B, N=4, 0%
BCP-ALL,N=894, 79%
T-ALL, N=234, 21%
Immunophenotype not known in 73 (6%) cases
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AgeAge--specific incidence of Tspecific incidence of T--ALLALL
0%
20%
40%
60%
80%
100%
13 14 15 16 17 18 19 20 21 22 23 24
T-ALLBCP-ALL
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Estimates of the incidence of Estimates of the incidence of TT--ALL specific abnormalitiesALL specific abnormalities
Abnormality Incidence
Children AYA Adults
22%
12%
2%
17%
2%
51%
4%
2%
SIL-TAL1/t(1;14) 16% 9%
t(11;14)(p13;q11)/LMO2 2% 0%
t(10;14)/TLX1 (HOX11) 4% 24%
t(5;14)/TLX3 (HOX11L2) 11% 6%
CALM-AF10 8% 0%
CDKN2A/B 46% 44%
MLL 5% 0%
NUP214-ABL1 3% 3%
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Cytogenetics of BCPCytogenetics of BCP--ALL in 13ALL in 13--24 year olds 24 year olds (n=837)(n=837)
IGH@12%
IGH@-CRLF23%
Normal13%
Other27%
HeH16%
Hypo (<40)3%iAMP21
4%CRLF2
3%
t(17;19)0%t(4;11)
3%
11q231%
t(1;19)3%
t(9;22)8%
t(12;21)4%
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Estimates of the incidence of BCPEstimates of the incidence of BCP--ALL ALL specific abnormalitiesspecific abnormalities
Abnormality No. Positive No. Tested Incidence <13 years >24 years
t(9;22) 68 781 9% 2% 20%t(1;19) 27 696 4% 3-5% 3-5%t(12;21) 25 531 5% 25% <1%t(17;19) 4 696 <1% <1% <1%t(4;11) 27 780 4% 2% 5-10%11q23 6 780 1% 2% 2%HeH 149 754 20% 35% 10%Hypo (<40) 23 754 3% 1% 5%iAMP21 26 531 5% <2% <2%IGH@ 31 216 14% 3% 15%IGH@-CRLF2 8 284 3% <1% ~5%CRLF2 5 115 4% ~5% ?Normal 102 696 15%Other 227 696 33%
4 cases had iAMP21 plus CRLF2 and 2 cases had iAMP21 plus an IGH translocation
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““OthersOthers””
Total n=227
• Abnormal 9p ~50%• +21 ~4%• +8 ~4%• +5 ~4%
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Duplication of chromosome 21 Duplication of chromosome 21 involving amplification of involving amplification of RUNX1RUNX1
Intrachromosomal amplification of chromosome 21 Intrachromosomal amplification of chromosome 21
iAMP21iAMP21
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ETV6RUNX1
Interphase FISH Metaphase FISH Metaphase FISH
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Demographic Profile of Demographic Profile of iAMP21 patientsiAMP21 patients
• Older children/Adolescents – Median age 10 years
• Common/Pre-B immunophenotype• Low WBC
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EFS of 28 iAMP21 patients on MRC ALL97EFS of 28 iAMP21 patients on MRC ALL97
0.00
0.20
0.40
0.60
0.80
1.00
Eve
nt F
ree
Sur
viva
l
0 1 2 3 4 5 6 7 8 9Time from diagnosis (years)
t(12;21)
HeH
Other11q23/MLL
<40 chr’s
t(9;22)
iAMP21
Moorman et al (2007) Blood 109:2327
88%
83%
72%61%
50%
38%29%
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Overall Survival - 5yr 69% (SE 8.6)
Event Free Survival - 5yr 26% (SE 8.3)
N=29
22 relapses (15 BM, 5 CNS, 2 BM&CNS)11 deaths (1 in 1st CCR)
October 2007 Update
0.00
0.25
0.50
0.75
1.00
Prop
ortio
n
0 1 2 3 4 5 6 7 8 9 10 11 12Years from Diagnosis
Leukaemia Research Cytogenetics Group
Outcome of iAMP21 patients on MRC ALL97
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DecisionDecision
To treat iAMP21 patients as highTo treat iAMP21 patients as high--risk risk in the current childhood trial: ALL2003in the current childhood trial: ALL2003
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iAMP21: outcome in ALL2003iAMP21: outcome in ALL20030.
000.
250.
500.
751.
00E
vent
Fre
e Su
rviv
al (%
)
0 1 2 3 4 5Years from diagnosis
Two deaths in remissionInfection following BMT One BM relapse
Post BMT9yr, Female
n=3933 treated as high risk14 received BMT
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iAMP21iAMP21Duplication of chromosome 21 Duplication of chromosome 21
involving amplification of involving amplification of RUNX1RUNX1
Every abnormal chromosome 21 has a different Every abnormal chromosome 21 has a different morphologymorphology
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7256
7619
8983
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BAC BAC ProbesmBAND G-band
A
B
C
D
E
F
A B C D E F
mBANDINGmBANDINGG bandingG banding
Robinson et al (2007) Genes Chromosomes Cancer 46:318-26
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A double-strand DNA break results in loss of atelomere and the formation of an unstable chromosome
Following replication the two sister chromatids fuse to form a dicentric chromosome
During anaphase this dicentric pulls apart resulting in breakage of the fusion bridge and production of an unstable chromosome with an inverted repeat
This process is repeated until the chromosome becomes stabilised by gaining a telomere. In this way it is possible to generate a chromosome with ladder like amplification.
Telomere
Centromere
RUNX1
KEY
The BreakageThe Breakage--FusionFusion--Bridge cycleBridge cycle
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iAMP21iAMP21• iAMP21 defines a distinct patient subgroup of older
children/young adults with a poor prognosis• Chromosomal instability gives rise to complex
intrachromosomal rearrangements of chromosome 21• Genome wide they show the same abnormalities of B-
cell differentiation genes• No obvious differentially expressed genes• Studies are in progress to determine the initiating
mechanism • Currently FISH with probes
directed to RUNX1 is the only reliable diagnostic method
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Normal 14
der(14)
der(19)
IGH@
Normal 19
BCL3
IGH@ IGH@ translocations in BCPtranslocations in BCP--ALLALL
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RP11-270I13
Normal 19
der(19)
der(14)Normal 19
der(19)
der(14)
CEBPA
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Within 6 nucleotides
IGH@-CEBP family
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IGH Testing in ALL by Age (n=1,304)IGH Testing in ALL by Age (n=1,304)3% <10 yrs, 14% >10 years3% <10 yrs, 14% >10 years
NB Selected screeningNB Selected screening
2522
1 421
27
0
100
200
300
400
500
600
700
800
900
0-9 10-14 15-19 20-24 25-29 30
Age Group
Num
ber o
f pat
ient
s
Normal Translocation
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t(14;19)(q32;q13)
der(19)
der(14)CEBPA
t(8;14)(q11;q32)CEBPD der(8)
der(14)
t(14;20)(q32;q13)CEBPB
der(20)
der(14)
t(14;14)(q11;q32)CEBPEder(14)
der(14)IGH@
translocations
IGH@IGH@--CEBP CEBP familyfamily
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der(19)
der(14)
IGH@-CEBPG
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IGH@translocations
t(8;14)(q11;q32)
t(14;19)(q32;q13)inv(14)(q11q32)
t(14;20)(q32;q13)
t(14;14)(q11;q32)
IGH@-CEBP family
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0
1
2
3
4
5
6
7
8
9
t(8;14
)t(8
;14)
t(14;2
0)H
L60M
UTZ5
REH
SD1
TANO
UEPER36
5
ALL pati
ent (
C)
ALL pati
ent (
M)
BM
Samples
Fol
d C
han
ge
CEBPB
CEBPD
qRTPCR
IGH@IGH@--CEBP CEBP familyfamily
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Translocation M:Fratio
Age range(median)
WBC rangex109/L
(median)
Current statuswhere available
t(14;19)(q32;q13) 2:7 10-44(19)
1-71(5)
1 dead4 CR
t(14;19)(q32;q13) 0:1 32 94 NA
t(14;20)(q32;q13) 1:2 13-35(15)
3-103(75)
2 CR
t(8;14)(q11;q32) 5:5 3-49(14)
2-375(7)
1 dead2 CR
t(14;14)(q11;q32)inv(14)(q11q32)
4:0 15-45(20)
1-24(13)
3 CR
IGH@IGH@--CEBP CEBP familyfamily
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Four IGH@ translocations
Involve five partner genes from the same gene family – CCAAT enhancer binding-proteins
One subtype of haematological disease, B-cell precursor ALL in older children and young adults
Basic leucine zipper transcription factors implicated in proliferation and differentiation
Expressed in haematopoietic system – control of myeloid differentiation
Tumour suppressor and oncogenic effects in leukaemogenesis
Summary – IGH@-CEBP family
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IGH@IGH@--ID4ID4
der(6)Normal 6
der(14)ID4
Centromere Telomere
A B
bHLH family of transcription factors – inhibitory proteins which regulate growth, differentiation, senescence and apoptosis
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• qRTPCR
020406080
100120140160
6120 16503 Normal Thyroid BCP-ALLpatient without
t(6;14)
BCP-ALLpatient without
t(6;14)
Normal bonemarrow
Samples
Fold
cha
nge
ID4
IGH@-ID4
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IGH@IGH@--ID4ID4
Patients• 13 BCP-ALL patients – recurrent
translocation• Low WBC (median 3x109/l,
range 1-11x109/l)• Age higher than expected for BCP-ALL
(median 16 yrs, range 6-48 years)
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IGH@IGH@--EPOREPOR
EPORC10orf39
G248P81743H6G248P85762A4 G248P81603G11
G248P82252A3
RGL3LPPR2Telomere Centromere
G248P89814C12
der(14) der(19)
(C)
5kb
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IGH@-EPOR
0
50
100
150
200
250
300
350
1067
2 diag
nosis
1067
2 rem
ission
(1)
1067
2 rela
pse
1067
2 rem
ission
(2)
All with
out tr
anslo
catio
nIG
H posit
ive ALL
High H
yperd
iploid
Saliva
ry BMFo
ld C
hang
e
EPOR
• qRTPCR
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~900Kb~250Kb
IGH@CRLF2
50Kb
wcpX wcpY
IGH@IGH@--CRLF2CRLF2TSLP TSLP ((thymicthymic stromalstromal derived derived lymphopoietinlymphopoietin))
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IGH@-CRLF2
• 33 patients
• BCP-ALL • CD34+ and CD33+
• Median age 16yrs (range 3-76yrs)
266 4 t(X;14)(p22;q32)
t(Y;14)(p11;q32)
Unknown
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IGH@-CRLF2
11 patients
27 BCP-ALL cell lines – 2 with t(Y;14)
i
L1477/04 BCP-ALL cell line
7243
L326/05
L1200/028765
7116
7108
12882
L759/02
CRLF2 CSF2RA10kb
PAR1PAR2
L889/01
11687
BCP-ALL cell line
P2RY8
152kbYp11.32
• LDI-PCRXp22.33
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IGH@-CRLF2
HIGH
low
• Expression
Patien
ts with
tran
sPati
ent w
ithout tr
ans
Cell lin
es w
ith tr
ans
Cell lin
es w
ithout tr
ans
Normal
bone marr
ow
0123456789
101112131415161718192021
p<0.0001 p<0.0001
Del
ta C
t val
ues
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IGH@IGH@--CRLF2CRLF2Children (n=19)10 events: 8 relapses (7 died);
2 non-remitter/early death9 patients on ALL2003 – all in 1st CCR
0.00
0.25
0.50
0.75
1.00
Pro
porti
on S
urvi
ving
Eve
nt F
ree
0 2 4 6Years from diagnosis
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IGH@ Partners
3p14 - FOXP1
2p13 - BCL11A
4p16 - FGFR34p16 - WHSC14p13 - RHOH
BCP-ALL
Previously reported
Published by LRCG and collaborators
On-going
Mature leukaemia/lymphoma
1q21- MUC11q24 - LHX4
1p34 – LAPTM5 1p22 - BCL10
1q21- FCGR2B1q21 - BCL9
3q27 - BCL6
6p25 - IRF46p22 - ID4*6p21 - CCND3
7q21 - CDK67q21 - ERVWE1
8q11 - CEBPD8q24 – MYC 9p13 - PAX5
10q24 - NFKB211q13 - CCND1
11q23 - DDX611q23 - PCSK7
11q23 - PAFHA1B212q23 - CHST11
12p13 – BCL114q11 - CEBPE14q11 - TCRA
15q12 - BCL816q23 - MAF
18q21 - BCL218q21 - MALT1
19q13 - CEBPA19q13 - CEBPG
19q13 - BCL3
20q11 - MAFB20q13 - CEBPB
22q11 - IGL
5q31 - IL3
1q21 – ITRA119p13 - EPOR
17q21 – IGF2BP1
Xp22/Yp11 – CRLF2
7p14 – TRG@
IGH@Translocations
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IGH@ Partnersin BCP-ALL
BCP-ALL
Previously reported
Published by LRCG and collaborators
On-going
1q24 - LHX4
1q21 - BCL9
8q11 - CEBPD
14q11 - CEBPE
20q13 - CEBPB
5q31 - IL3
6p22 - ID4*
12p13 – BCL1
19q13 - CEBPA19q13 - CEBPG
19p13 - EPOR
Xp22/Yp11 – CRLF2
7p14 – TRG@
IGH@Translocations
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IGH@ IGH@ translocationstranslocations
• IGH@ is a promiscuous locus: common link to the genes involved and their interrelated pathways
• Majority of patients are older children or adolescents
• Cytogenetics still identifies new translocations and subgroups
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Conclusions to genetics of AYAConclusions to genetics of AYA
• They show abnormalities in common with childhood ALL, although the incidences are different
• There are some novel abnormalities emerging which are common in this age group
• Detailed analysis may highlight some as these as specific targets for therapy
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AcknowledgementsAcknowledgements
Newcastle, UKNewcastle, UK•• Anthony MoormanAnthony Moorman•• Leukaemia Research Leukaemia Research
Cytogenetics GroupCytogenetics Group
Leicester, UKLeicester, UK•• Martin DyerMartin Dyer
Kiel, GermanyKiel, Germany•• Reiner SiebertReiner Siebert
Paris, FranceParis, France•• Olivier BernardOlivier Bernard
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To findTo find IGH@IGH@ positive positive casescases
Normal 14 der(14)
der(19)
Screen by FISH with IGH@ breakapart probe
Not: • ETV6-RUNX1 positive• High hyperdiploidy• BCR-ABL1• t(1;19)
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IGH@-CRLF2
13 14 15 16 17 18 19 20 21 22
1 2 3 4 5 6 7 8 9 10 11 12
PAX5
CDKN2A/B
IKZF1
• aCGH
X Y
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IGH@-CRLF2
0
0.2
0.4
0.6
0.8
1
1.2
siCRLF2 Negative control siRNA
Fold
cha
nge
siMENIN + CRLF2 AbsiCRLF2 + CRLF2 Ab
siCRLF2 + IgG2 Ab
siMENIN + CRLF2 AbsiCRLF2 + CRLF2 Ab
siCRLF2 + IgG2 Ab
• Knockdown
Untreated unstained
Untreated unstained
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IGH@-CRLF2
Gated
0
10
20
30
40
50
60
70
80
90
UL UR LL LR
Quadrant
% o
f cel
ls
siCRLF2siMENINMOCK
siMENIN + pSTAT5 AbsiCRLF2 + pSTAT5 Ab
Isotype control + pSTAT5 Ab
No difference in;
Apoptosis
pSTAT5 Why?
Cell cycle
• Biological consequences
siCRLF2 siMENIN
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IGH@-CRLF2• JAK2 mutation?
WT - TTCTGCTTATCAGAGAAGAA
GGA - R683G
TTC - I682F
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IGH@-CRLF2
hCRLF2 – number and diameter
Data from Dr Melania Capasso
Mouse fetal liver cells
• Retroviral transfection
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Data from Dr Melania Capasso
•CRLF2 expressing cells are less differentiated compared to EV cells
•Low CRLF2 expressing cells are more differentiated than high CRLF2 expressing cells
CD43+/CD19+
IGH@-CRLF2
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Numbers of AYA by Trial and Year of diagnosis (N=1,179)
0
20
40
60
80
100
1990
1991
1992
1993
1994
1995
1996
1997
1998
1999
2000
2001
2002
2003
2004
2005
2006
2007
2008
2009
Year of diagnosis
Num
ber o
f pat
ient
s
ALL2003 (N=335) ALL97 (N=243) UKALLXI (N=107) UKALLXII (N=493)