Detail
Article
Online article
FT
Medvik - BMC
  • Something wrong with this record ?

Higher-order immunoglobulin repertoire restrictions in CLL: the illustrative case of stereotyped subsets 2 and 169

K. Gemenetzi, F. Psomopoulos, AA. Carriles, M. Gounari, C. Minici, K. Plevova, LA. Sutton, M. Tsagiopoulou, P. Baliakas, K. Pasentsis, A. Anagnostopoulos, R. Sandaltzopoulos, R. Rosenquist, F. Davi, S. Pospisilova, P. Ghia, K. Stamatopoulos, M....

. 2021 ; 137 (14) : 1895-1904. [pub] 20210408

Language English Country United States

Document type Journal Article, Research Support, Non-U.S. Gov't

Persistent link   https://www.medvik.cz/link/bmc22004462

Chronic lymphocytic leukemia (CLL) major stereotyped subset 2 (IGHV3-21/IGLV3-21, ∼2.5% of all cases of CLL) is an aggressive disease variant, irrespective of the somatic hypermutation (SHM) status of the clonotypic IGHV gene. Minor stereotyped subset 169 (IGHV3-48/IGLV3-21, ∼0.2% of all cases of CLL) is related to subset 2, as it displays a highly similar variable antigen-binding site. We further explored this relationship through next-generation sequencing and crystallographic analysis of the clonotypic B-cell receptor immunoglobulin. Branching evolution of the predominant clonotype through intraclonal diversification in the context of ongoing SHM was evident in both heavy and light chain genes of both subsets. Molecular similarities between the 2 subsets were highlighted by the finding of shared SHMs within both the heavy and light chain genes in all analyzed cases at either the clonal or subclonal level. Particularly noteworthy in this respect was a ubiquitous SHM at the linker region between the variable and the constant domain of the IGLV3-21 light chains, previously reported as critical for immunoglobulin homotypic interactions underlying cell-autonomous signaling capacity. Notably, crystallographic analysis revealed that the IGLV3-21-bearing CLL subset 169 immunoglobulin retains the same geometry and contact residues for the homotypic intermolecular interaction observed in subset 2, including the SHM at the linker region, and, from a molecular standpoint, belong to a common structural mode of autologous recognition. Collectively, our findings document that stereotyped subsets 2 and 169 are very closely related, displaying shared immunoglobulin features that can be explained only in the context of shared functional selection.

References provided by Crossref.org

000      
00000naa a2200000 a 4500
001      
bmc22004462
003      
CZ-PrNML
005      
20220127145222.0
007      
ta
008      
220113s2021 xxu f 000 0|eng||
009      
AR
024    7_
$a 10.1182/blood.2020005216 $2 doi
035    __
$a (PubMed)33036024
040    __
$a ABA008 $b cze $d ABA008 $e AACR2
041    0_
$a eng
044    __
$a xxu
100    1_
$a Gemenetzi, Katerina $u Institute of Applied Biosciences, Centre for Research and Technology Hellas, Thessaloniki, Greece $u Department of Molecular Biology and Genetics, Democritus University of Thrace, Alexandroupolis, Greece
245    10
$a Higher-order immunoglobulin repertoire restrictions in CLL: the illustrative case of stereotyped subsets 2 and 169 / $c K. Gemenetzi, F. Psomopoulos, AA. Carriles, M. Gounari, C. Minici, K. Plevova, LA. Sutton, M. Tsagiopoulou, P. Baliakas, K. Pasentsis, A. Anagnostopoulos, R. Sandaltzopoulos, R. Rosenquist, F. Davi, S. Pospisilova, P. Ghia, K. Stamatopoulos, M. Degano, A. Chatzidimitriou
520    9_
$a Chronic lymphocytic leukemia (CLL) major stereotyped subset 2 (IGHV3-21/IGLV3-21, ∼2.5% of all cases of CLL) is an aggressive disease variant, irrespective of the somatic hypermutation (SHM) status of the clonotypic IGHV gene. Minor stereotyped subset 169 (IGHV3-48/IGLV3-21, ∼0.2% of all cases of CLL) is related to subset 2, as it displays a highly similar variable antigen-binding site. We further explored this relationship through next-generation sequencing and crystallographic analysis of the clonotypic B-cell receptor immunoglobulin. Branching evolution of the predominant clonotype through intraclonal diversification in the context of ongoing SHM was evident in both heavy and light chain genes of both subsets. Molecular similarities between the 2 subsets were highlighted by the finding of shared SHMs within both the heavy and light chain genes in all analyzed cases at either the clonal or subclonal level. Particularly noteworthy in this respect was a ubiquitous SHM at the linker region between the variable and the constant domain of the IGLV3-21 light chains, previously reported as critical for immunoglobulin homotypic interactions underlying cell-autonomous signaling capacity. Notably, crystallographic analysis revealed that the IGLV3-21-bearing CLL subset 169 immunoglobulin retains the same geometry and contact residues for the homotypic intermolecular interaction observed in subset 2, including the SHM at the linker region, and, from a molecular standpoint, belong to a common structural mode of autologous recognition. Collectively, our findings document that stereotyped subsets 2 and 169 are very closely related, displaying shared immunoglobulin features that can be explained only in the context of shared functional selection.
650    _2
$a krystalografie rentgenová $7 D018360
650    _2
$a regulace genové exprese u leukemie $7 D015973
650    _2
$a genová přestavba $7 D015321
650    _2
$a geny pro těžké řetězce imunoglobulinů $x genetika $7 D050438
650    _2
$a HEK293 buňky $7 D057809
650    _2
$a lidé $7 D006801
650    _2
$a chronická lymfatická leukemie $x genetika $7 D015451
650    _2
$a molekulární modely $7 D008958
650    _2
$a proteinové domény $7 D000072417
650    _2
$a receptory antigenů B-buněk $x chemie $x genetika $7 D011947
650    _2
$a somatická hypermutace imunoglobulinových genů $7 D027041
655    _2
$a časopisecké články $7 D016428
655    _2
$a práce podpořená grantem $7 D013485
700    1_
$a Psomopoulos, Fotis $u Institute of Applied Biosciences, Centre for Research and Technology Hellas, Thessaloniki, Greece $u Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden
700    1_
$a Carriles, Alejandra A $u Biocrystallography Unit, Division of Immunology, Transplantation and Infectious Diseases, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Ospedale San Raffaele, Milan, Italy
700    1_
$a Gounari, Maria $u Institute of Applied Biosciences, Centre for Research and Technology Hellas, Thessaloniki, Greece
700    1_
$a Minici, Claudia $u Biocrystallography Unit, Division of Immunology, Transplantation and Infectious Diseases, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Ospedale San Raffaele, Milan, Italy
700    1_
$a Plevova, Karla $u Hematology and Oncology, Department of Internal Medicine, University Hospital Brno, Brno, Czech Republic $u Faculty of Medicine, Central European Institute of Technology (CEITEC), Masaryk University, Brno, Czech Republic
700    1_
$a Sutton, Lesley-Ann $u Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden
700    1_
$a Tsagiopoulou, Maria $u Institute of Applied Biosciences, Centre for Research and Technology Hellas, Thessaloniki, Greece
700    1_
$a Baliakas, Panagiotis $u Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden
700    1_
$a Pasentsis, Kostas $u Institute of Applied Biosciences, Centre for Research and Technology Hellas, Thessaloniki, Greece
700    1_
$a Anagnostopoulos, Achilles $u Hematopoietic Cell Transplantation Unit, Department of Hematology, G. Papanikolaou Hospital, Thessaloniki, Greece
700    1_
$a Sandaltzopoulos, Raphael $u Department of Molecular Biology and Genetics, Democritus University of Thrace, Alexandroupolis, Greece
700    1_
$a Rosenquist, Richard $u Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden $u Clinical Genetics, Karolinska University Laboratory, Karolinska University Hospital, Stockholm, Sweden
700    1_
$a Davi, Frederic $u Department of Hematology, Hôpital Pitié-Salpêtrière and Sorbonne University, Paris, France
700    1_
$a Pospisilova, Sarka $u Hematology and Oncology, Department of Internal Medicine, University Hospital Brno, Brno, Czech Republic $u Faculty of Medicine, Central European Institute of Technology (CEITEC), Masaryk University, Brno, Czech Republic
700    1_
$a Ghia, Paolo $u Medical Oncology, Università Vita-Salute San Raffaele, Milan, Italy; and $u Strategic Research Program on CLL, B Cell Neoplasia Unit, Division of Experimental Oncology, IRCCS Ospedale San Raffaele, Milan, Italy
700    1_
$a Stamatopoulos, Kostas $u Institute of Applied Biosciences, Centre for Research and Technology Hellas, Thessaloniki, Greece $u Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden
700    1_
$a Degano, Massimo $u Biocrystallography Unit, Division of Immunology, Transplantation and Infectious Diseases, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Ospedale San Raffaele, Milan, Italy
700    1_
$a Chatzidimitriou, Anastasia $u Institute of Applied Biosciences, Centre for Research and Technology Hellas, Thessaloniki, Greece $u Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden
773    0_
$w MED00000807 $t Blood $x 1528-0020 $g Roč. 137, č. 14 (2021), s. 1895-1904
856    41
$u https://pubmed.ncbi.nlm.nih.gov/33036024 $y Pubmed
910    __
$a ABA008 $b sig $c sign $y p $z 0
990    __
$a 20220113 $b ABA008
991    __
$a 20220127145219 $b ABA008
999    __
$a ok $b bmc $g 1751811 $s 1155611
BAS    __
$a 3
BAS    __
$a PreBMC
BMC    __
$a 2021 $b 137 $c 14 $d 1895-1904 $e 20210408 $i 1528-0020 $m Blood $n Blood $x MED00000807
LZP    __
$a Pubmed-20220113

Find record

Citation metrics

Archiving options