Download - Immunoglobulin genes in CLL - ericll.org
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Kostas Stamatopoulos
Institute of Applied Biosciences CERTH, Thessaloniki
Immunoglobulin genes in CLL biological aspects
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CLL is a clone of mature B cells
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Mature B cells interact with the microenvironment
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CLL cells are doing the same!
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microenvironmental interactions
receptors
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B cell receptor immunoglobulin a unique molecular signature for every Β cell clone
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Immunoglobulins are very diverse
Combinatorial
Junctional
Somatic hypermutation
L IGKV IGKJ IGHC
5’ 3’
5’ 3’
~ 6,3 x 106 combinations ~ 3,5 x 105 combinations
Heavy chain (IGH) Light chain (IGL)
L IGHV IGHD IGHJ IGHC
5’ 3’
39-46 IGHV x 23 IGHD x 6 IGHJ
~ 6300 combinations ~185+165 combinations 5’ 3’
L IGLV IGLJ IGLC
5’ 3’
33-37 IGKV x 5 IGKJ/ 30-33 IGLV x 4-5 IGLJ
Mathematical chance that two different B cell clones will share the same IG
0 , 0 0 0 0 0 0 0 0 0 0 0 1 %
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IG genes a unique molecular identity for CLL
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IG genes in CLL
why?
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Hamblin et al, Blood 1999
Damle et al, Blood 1999
CLL - better with mutated IG receptors
M
UM
M
UM
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why?
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an immunological trajectory from primary to 3D structures
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IGH locus
46 functional IGHV genes
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0
2
4
6
8
10
12
14
16
18
20
immunoglobulin gene frequencies
46 functional IGHV genes
if it happened by chance
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0
2
4
6
8
10
12
14
V1-
18
V1-
2
V1-
24
V1-
3
V1-
45
V1-
46
V1-
58
V1-
69
V1-
8
V2-
26
V2-
5
V2-
70
V3-
7
V3-
9
V3-
11
V3-
13
V3-
15
V3-
19
V3-
20
V3-
21
V3-
23
V3-
30
V3-
30-3
V3-
33
V3-
43
V3-
48
V3-
49
V3-
53
V3-
64
V3-
66
V3-
72
V3-
73
V3-
74
V4-
30-2
V4-
30-4
V4-
31
V4-
34
V4-
39
V4-
4
V4-
59
V4-
61
V4-
b
V5-
51
V5-
a
V6-
1
V7-
4-1
Fais et al. J Clin Invest 1998; Murray et al. Blood 2008; Agathangelidis et al. Blood 2012
it’s not happening by chance!
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0
2
4
6
8
10
12
14
V1-
18
V1-
2
V1-
24
V1-
3
V1-
45
V1-
46
V1-
58
V1-
69
V1-
8
V2-
26
V2-
5
V2-
70
V3-
7
V3-
9
V3-
11
V3-
13
V3-
15
V3-
19
V3-
20
V3-
21
V3-
23
V3-
30
V3-
30-3
V3-
33
V3-
43
V3-
48
V3-
49
V3-
53
V3-
64
V3-
66
V3-
72
V3-
73
V3-
74
V4-
30-2
V4-
30-4
V4-
31
V4-
34
V4-
39
V4-
4
V4-
59
V4-
61
V4-
b
V5-
51
V5-
a
V6-
1
V7-
4-1
Fais et al. J Clin Invest 1998; Murray et al. Blood 2008; Agathangelidis et al. Blood 2012
V1-69 U-CLL
V4-34 M-CLL
V3-21 Borderline
SHM status
different IGHV genes differential SHM status
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antigen selection
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Unmutated CLL: polyreactive receptors many opportunities for activation
Herve et al. J Clin Invest 2005; Seiler et al. Blood 2009
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Attenuated signaling in good prognosis CLL
Bad prognosis
Survival, proliferation
Good prognosis
Zupo et al, 1996; Chen et al, 2002; Lanham et al, 2003; Mockridge et al, 2007 Muzio et al, 2008; Krysov et al, 2012; Ntoufa et al. 2012; Chatzouli et al, 2014
Appolonio et al, 2014; Ntoufa et al, 2016
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fact
CLL - better with mutated IG receptors
always?
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IGHV3-21 CLL a distinct disease variant?
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~50% of IGHV3-21 CLL carry restricted BcR IG
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Stereotyped
repeated with limited or no variation
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Probability that two different B cell clones carry identical BcRs
1:10-12
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stereotypy in CLL is not happening by chance
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Uppsala
Bournemouth
Copenhagen
Athens
Paris
New York
Brno
Montpellier
London
Milan
Rotterdam
2012
11 institutes 7424 patients
Thessaloniki
BcR stereotypy: 33% 19 major subsets
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Montpellier
Uppsala
Bournemouth
London Copenhagen
Turin
Athens
Rotterdam
Milan
Paris
New York
Brno Ulm
Kiel
Athens-Un
Moscow
Novara Rochester, MN
Belfast
Belgrade Padova
Barcelona
2019 BcR stereotypy: 41%
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stereotyped subsets
distinct clinical variants of CLL
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BcR stereotypy refines prognostication in CLL
Distinct clinical outcomes for subsets #1, #2 and #4, independently of genomic aberrations or SHM status
Baliakas et al. Lancet Haematol. 2014
All express IGHV4-34, all concern IG mutated CLL, yet the outcome is different
Xochelli et al. Clin Cancer Res 2017
Subset #2 is as bad as CLL with TP53 aberrations though essentially devoid of such lesions
Baliakas et al. Blood 2015
Subset #8: the highest risk for Richter’s transformation amongst all CLL
Rossi et al. Clin Cancer Res. 2009
#4
#1
#2
0 5 10 15 20 25 30
Time years
0%
25%
50%
75%
100%
% u
ntr
ea
ted
#2, n=212 del(17p), n=284
p=0.5
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is there a biological explanation?
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the unpleasant extreme
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Subset #2: the most aggressive CLL variant?
Baliakas et al. Lancet Haematol 2014
#2
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only subset #2 is nasty
not just any IGHV3-21
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Subset #2 as bad as TP53 aberrant CLL
0 5 10 15 20 25 30
Time years
0%
25%
50%
75%
100%
% u
ntr
ea
ted
#2, n=212 del(17p), n=284
p=0.5Baliakas et al; Blood 2015
do not blame TP53 loss/mutation
Malcikova et al. BJH 2014
Sutton et al. Haematologica 2016 0%
10%
20%
30%
40%
50%
# 1 # 2 # 3 # 5 # 6 # 7 # 8
TP53 mutations in major stereotyped subsets
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SF3B1 mutations are remarkably enriched in subset #2
Strefford et al. Leukemia 2013 Rossi et al. Blood 2013
44.5% 45.4%
0
10
20
30
40
50
Subset #1 Subset #2 Subset #80
10
20
30
40
50
Subset #1 Subset #2 Subset #8
Rossi et al. Blood 2012
A distinctive oncogenetic signature for subset #2
5%
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Baliakas et al;. Lancet Haematol 2014
Subset-biased landscapes of genomic aberrations
trisomy 12
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Subset-biased landscapes of genomic aberrations
Sutton et al. Haematologica 2016
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distinctive immunogenetic signatures
distinctive
oncogenetic signatures
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the pleasant extreme
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Subset #4: the most indolent CLL variant?
Baliakas et al. Lancet Haematol 2014; Xochelli et al. Clin Cancer Res 2017
#4
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Subset #2 mAbs homodimerize
Subset #4 mAbs homodimerize
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Distinct homotypic BcR interactions shape the outcome of CLL
CLL BcR immunoglobulins initiate intracellular signaling through homotypic interactions between epitopes that are specific for each stereotyped subset.
The molecular details of the BcR-BcR interactions determine the clinical course
stronger affinities and longer half-lives in indolent cases
weaker, short-lived contacts in aggressive cases
The diversity of homotypic BcR contacts leading to cell-autonomous signaling reconciles the existence of a shared pathogenic mechanism with the biological and clinical heterogeneity of CLL
Minici et al. Nat Commun 2017
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final words?
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Baliakas et al. Leukemia 2015
all negative and/or del(13q)
all negative and/or del(13q)
M-CLL
U-CLL
Complex interactions between cell-intrinsic and cell-extrinsic processes impact on CLL outcome
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B cell receptor immunoglobulin a unique molecular signature for every Β cell clone
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B cell receptor immunoglobulin key to understanding and treating CLL
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a secret for success?
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join forces!
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San Raffaele, Milan Paolo Ghia Lydia Scarfo Marta Muzio Karolinska Institute, Stockholm Richard Rosenquist Lesley-Ann Sutton Uppsala University Panagiotis Baliakas Pitié Salpêtrière, Paris Fred Davi Nikea General Hospital, Athens Chrysoula Belessi Feinstein Institute, Manhasset Nicholas Chiorazzi
ΙΝAΒ | CERTH, Thessaloniki Anastasia Hadzidimitriou Andreas Agathangelidis |Maria Gounari Eva Minga | Stavroula Ntoufa Anna Vardi | Aliki Xochelli Chrysi Galigalidou | Katerina Gemenetzi Elisavet Vlachonikola| Laura Zaragoza G. Papanicolaou Hospital, Thessaloniki Niki Stavroyianni Achilles Anagnostopoulos IMGT, Montpellier Marie-Paule Lefranc Veronique Giudicelli Sofia Kossida Erasmus MC, Rotterdam Anton Langerak