Biomarkers in Chronic Lymphocytic Leukemia: the art of synthesis. CLL Immunogenetics. Overview. Anastasia Chatzidimitriou
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1 Biomarkers in Chronic Lymphocytic Leukemia: the art of synthesis CLL Immunogenetics Overview Anastasia Chatzidimitriou Belgrade March 17, 2018
2 B cells: multiple receptors
3 B cell receptor IG unique signature of each B cell
4 HEAVY CHAIN IG synthesis the LEGO approach 150 FUNCTIONAL IG GENES V D J C V J C LIGHT CHAIN 5 ' 3 ' 5 ' 3 ' x 2 3 x x 5 K a p p a x 4-5 L a m b d a 6300 POTENTIAL RECOMBINATIONS POTENTIAL RECOMBINATIONS Exonuclease activity Nucleotide insertion Somatic hypermutation 3.5 x ' 3 ' 5 ' 3 ' 6.3 x 10 6 x1000 IMGT Repertoire,
5 Immunology & Mathematics Probability that two different B cell clones carry identical B cell receptors Negligible!! 1: %
6 B cells turning nasty: CLL the IG receptor act as a unique marker for the tumor clone
7 Antigen selection in CLL ontogeny and evolution immunogenetic evidence Skewed IG gene repertoire Fais et al. J Clin Invest 1998; Agathangelidis et al. Blood 2012
8 IG gene repertoire in CLL 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 V V3-33 V3-43 V3-48 V3-49 V3-53 V3-64 V3-66 V3-72 V3-73 V3-74 V V V4-31 V4-34 V4-39 V4-4 V4-59 V4-61 V4-b V5-51 V5-a Agathangelidis et al. Blood 2012 V6-1 V7-4-1
9 Antigen selection in CLL ontogeny and evolution the immunogenetic evidence Skewed IG gene repertoire Fais et al. J Clin Invest 1998; Agathangelidis et al. Blood 2012 Division of CLL cases into subgroups with different outcome based on IGHV gene mutations Damle et al. Blood 1999; Hamblin et al. Blood 1999
10 CLL - better with mutated IG receptors UM M UM M Hamblin et al, Blood 1999 Damle et al., Blood 1999
11 Oscier et al. The clinical significance of NOTCH1 and SF3B1 mutations in the UK LRF CLL4 trial. Blood 2013 Stilgenbauer et al. Gene mutations and treatment outcome in chronic lymphocytic leukemia: results from the CLL8 trial. Blood 2014
12 FCR: plateau in patients with mutated IGHV genes IGHV-M IGHV-UM and/or del(11q) del(17p) Rossi et al. Blood 2015
13 fact CLL - better with mutated IG receptors always?
14 IGHV3-21 CLL a distinct disease variant?
15 ~50% of IGHV3-21 CLL carry restricted BcR IG
16 Stereotyped repeated with limited or no variation
17 2012 New York 11 institutes 7424 patients Milan Montpellier Uppsala Copenhagen London Rotterdam Bournemouth Paris Brno Thessaloniki 7596 IG sequences BcR stereotypy: 33% 19 major subsets Athens
18 Stereotypy: a chance event? Mathematical chance that two different B cell clones might share the same BcR 1:10-12
19 Stereotypy in CLL: a chance event? Not by any chance!
20 2015 BcR stereotypy: 32% Rochester, MN New York Uppsala Belfast Kiel Copenhagen London Rotterdam Bournemouth Ulm Paris Brno Novara Belgrade Turin Padova Milan Barcelona Montpellier Athens Athens-Un Moscow
21 8593 patients
22 Subsets are distinct clinical entities Baliakas et al. Lancet Haematol 2014
23 Subset #4: the most indolent CLL variant? #4 Baliakas et al. Lancet Haematol 2014
24 100% Subset #2 75% #2, n=212 del(17p), n=284 the nastier of all? Baliakas et al. Lancet Haematol 2014 % untreated 50% p=0.5 Baliakas et al. Blood % 0% % Time years TP53 mutations in major stereotyped subsets 40% 30% Do not blame it on TP53 loss/mutation Malcikova et al. BJH % 10% 0% # 1 # 2 # 3 # 5 # 6 # 7 # 8
25 Subset #2 is nasty - not just any IGHV3-21 Subset #2 is bad regardless of SHM status
26 Advances in chemoimmunotherapy did not benefit patients in CLL subset #2 Baliakas P et al. Haematologica 2018
27 Different subsets distinct recurrent mutations Sutton et al, Haematologica 2016
28 Different subsets distinct cytogenetics del(11q) Baliakas et al; Lancet Haematol 2014 U-CLL IGHV1-69 IGHV4-34 M-CLL
29 Different subsets distinct cytogenetics del(17p) Baliakas et al; Lancet Haematol 2014 U-CLL IGHV1-69 IGHV4-34 M-CLL
30 Different Igs different clinicobiological profiles variable IG SHM del(13q) & del(11q) SF3B1 mutations #2 12% unmutated IG promiscuous antigen reactivity trisomy 12, t(14;19) NOTCH1 mutations risk of Richter s transformation #8 major subsets #1 unmutated IG propensity to develop ITP CD38 and ZAP70 del(17p) #4 mutated IG no CD38 and ZAP70 low genomic complexity low cell proliferation young age at diagnosis Agathangelidis et a, Blood 2012; Strefford et al, Leukemia 2013; Rossi et al, Blood 2013; Baliakas et al, Lancet Haematol 2014; Baliakas et al, Blood 2015; Gounari et al, Blood 2015; Ntoufa et al, J Immunol 2016; Papakonstantinou et al, Oncotarget 2016; Sutton et al, Haematologica 2016
31 Antigen selection in CLL ontogeny and evolution immunogenetic evidence Skewed IG gene repertoire Fais et al. J Clin Invest 1998; Agathangelidis et al. Blood 2012 Division of CLL cases into subgroups with different outcome based on IGHV gene mutations Damle et al. Blood 1999; Hamblin et al. Blood 1999 Groups of CLL cases with quasi-identical antigen-binding sites stereotyped BcRs Messmer et al J Exp Med 2004
32 B cell receptor immunoglobulin a unique molecular signature for the CLL clone
33 B cell receptor immunoglobulin key to understanding CLL
34 Biomarkers in Chronic Lymphocytic Leukemia: the art of synthesis CLL Immunogenetics Overview Anastasia Chatzidimitriou Belgrade March 17, 2018
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