Insertion of atypical glycans into the tumor antigen-binding site identifies DLBCLs with distinct origin and behavior.
Binding Sites
Cell Adhesion Molecules
/ chemistry
Complementarity Determining Regions
/ chemistry
Glycosylation
Humans
Lectins, C-Type
/ chemistry
Lymphoma, Large B-Cell, Diffuse
/ chemistry
Polysaccharides
/ analysis
Protein Interaction Domains and Motifs
Receptors, Cell Surface
/ chemistry
Tumor Cells, Cultured
Journal
Blood
ISSN: 1528-0020
Titre abrégé: Blood
Pays: United States
ID NLM: 7603509
Informations de publication
Date de publication:
28 10 2021
28 10 2021
Historique:
received:
09
04
2021
accepted:
03
08
2021
pubmed:
24
8
2021
medline:
15
12
2021
entrez:
23
8
2021
Statut:
ppublish
Résumé
Glycosylation of the surface immunoglobulin (Ig) variable region is a remarkable follicular lymphoma-associated feature rarely seen in normal B cells. Here, we define a subset of diffuse large B-cell lymphomas (DLBCLs) that acquire N-glycosylation sites selectively in the Ig complementarity-determining regions (CDRs) of the antigen-binding sites. Mass spectrometry and X-ray crystallography demonstrate how the inserted glycans are stalled at oligomannose-type structures because they are buried in the CDR loops. Acquisition of sites occurs in ∼50% of germinal-center B-cell-like DLBCL (GCB-DLBCL), mainly of the genetic EZB subtype, irrespective of IGHV-D-J use. This markedly contrasts with the activated B-cell-like DLBCL Ig, which rarely has sites in the CDR and does not seem to acquire oligomannose-type structures. Acquisition of CDR-located acceptor sites associates with mutations of epigenetic regulators and BCL2 translocations, indicating an origin shared with follicular lymphoma. Within the EZB subtype, these sites are associated with more rapid disease progression and with significant gene set enrichment of the B-cell receptor, PI3K/AKT/MTORC1 pathway, glucose metabolism, and MYC signaling pathways, particularly in the fraction devoid of MYC translocations. The oligomannose-type glycans on the lymphoma cells interact with the candidate lectin dendritic cell-specific intercellular adhesion molecule 3 grabbing non-integrin (DC-SIGN), mediating low-level signals, and lectin-expressing cells form clusters with lymphoma cells. Both clustering and signaling are inhibited by antibodies specifically targeting the DC-SIGN carbohydrate recognition domain. Oligomannosylation of the tumor Ig is a posttranslational modification that readily identifies a distinct GCB-DLBCL category with more aggressive clinical behavior, and it could be a potential precise therapeutic target via antibody-mediated inhibition of the tumor Ig interaction with DC-SIGN-expressing M2-polarized macrophages.
Identifiants
pubmed: 34424958
pii: S0006-4971(21)01511-1
doi: 10.1182/blood.2021012052
pmc: PMC8554650
doi:
Substances chimiques
Cell Adhesion Molecules
0
Complementarity Determining Regions
0
DC-specific ICAM-3 grabbing nonintegrin
0
Lectins, C-Type
0
Polysaccharides
0
Receptors, Cell Surface
0
Types de publication
Journal Article
Research Support, N.I.H., Intramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1570-1582Commentaires et corrections
Type : CommentIn
Informations de copyright
© 2021 by The American Society of Hematology.
Références
Proc Natl Acad Sci U S A. 2005 Aug 2;102(31):10987-92
pubmed: 16037207
Biochim Biophys Acta Gen Subj. 2019 Oct;1863(10):1480-1497
pubmed: 31121217
J Biol Chem. 2007 Mar 9;282(10):7405-15
pubmed: 17197448
Immunol Rev. 2019 Sep;291(1):190-213
pubmed: 31402495
Proc Natl Acad Sci U S A. 2015 Nov 3;112(44):13447-54
pubmed: 26483459
Nat Struct Mol Biol. 2004 Jul;11(7):591-8
pubmed: 15195147
Blood. 2018 May 24;131(21):2307-2319
pubmed: 29666115
Mol Aspects Med. 2016 Oct;51:31-55
pubmed: 27086127
Nature. 2000 Feb 3;403(6769):503-11
pubmed: 10676951
N Engl J Med. 2002 Jun 20;346(25):1937-47
pubmed: 12075054
Cell. 2000 Mar 3;100(5):575-85
pubmed: 10721994
Nature. 2018 Aug;560(7718):387-391
pubmed: 29925955
N Engl J Med. 2018 Apr 12;378(15):1396-1407
pubmed: 29641966
Blood. 2020 Mar 12;135(11):834-844
pubmed: 31932843
Blood. 2015 Oct 15;126(16):1902-10
pubmed: 26194765
Proc Natl Acad Sci U S A. 2016 Dec 6;113(49):E7890-E7899
pubmed: 27856750
Blood. 2015 Oct 15;126(16):1911-20
pubmed: 26272216
Cancer Cell. 2020 Apr 13;37(4):551-568.e14
pubmed: 32289277
Nat Commun. 2018 Aug 17;9(1):3287
pubmed: 30120234
Br J Haematol. 2004 Mar;124(5):604-9
pubmed: 14871246
J Leukoc Biol. 2002 Mar;71(3):445-57
pubmed: 11867682
Cell. 1997 Sep 19;90(6):1073-83
pubmed: 9323135
Leukemia. 2006 Mar;20(3):530-4
pubmed: 16437152
Nat Med. 2015 Aug;21(8):922-6
pubmed: 26193343
Blood. 2002 Apr 1;99(7):2562-8
pubmed: 11895794
Proc Natl Acad Sci U S A. 2008 Sep 9;105(36):13520-5
pubmed: 18765795
Sci Rep. 2021 Jun 3;11(1):11676
pubmed: 34083646
Mol Immunol. 2008 Mar;45(6):1567-72
pubmed: 18022232
Cell. 2000 Mar 3;100(5):587-97
pubmed: 10721995
FEBS Lett. 2006 Nov 13;580(26):6123-31
pubmed: 17055489
Nat Immunol. 2018 Aug;19(8):871-884
pubmed: 29988090
Blood. 2015 May 21;125(21):3287-96
pubmed: 25784678
Proc Natl Acad Sci U S A. 2015 Mar 10;112(10):E1116-25
pubmed: 25713363
Immunol Rev. 2021 Jul;302(1):273-285
pubmed: 34060097
Nature. 2011 Mar 10;471(7337):189-95
pubmed: 21390126
J Immunol. 1988 Mar 1;140(5):1695-701
pubmed: 3162250
Proc Natl Acad Sci U S A. 2010 Oct 26;107(43):18587-92
pubmed: 20937880
Nat Genet. 2014 Feb;46(2):176-181
pubmed: 24362818
Cell Rep. 2018 Aug 21;24(8):1958-1966.e5
pubmed: 30134158
Blood. 2018 May 24;131(21):2297-2306
pubmed: 29666116
Blood. 2011 Oct 13;118(15):4111-9
pubmed: 21860028
Blood. 2017 Feb 9;129(6):759-770
pubmed: 28011673
Nat Rev Cancer. 2014 Aug;14(8):517-34
pubmed: 25008267
J Clin Oncol. 2019 Jan 20;37(3):190-201
pubmed: 30523716
Blood. 2005 Aug 15;106(4):1278-85
pubmed: 15878980
Curr Opin Struct Biol. 2017 Jun;44:125-133
pubmed: 28363124
Nature. 2017 Jun 8;546(7657):302-306
pubmed: 28562582
J Immunother Cancer. 2019 Oct 22;7(1):272
pubmed: 31640780