Reimann, Maurice, Schrezenmeier, Jens, Richter-Pechanska, Paulina, Dolnik, Anna, Hick, Timon Pablo, Schleich, Kolja, Cai, Xiurong, Fan, Dorothy N. Y., Lohneis, Philipp, Masswig, Sven, Denker, Sophy ORCID: 0000-0002-0736-6019, Busse, Antonia ORCID: 0000-0002-3470-6947, Knittel, Gero ORCID: 0000-0001-8395-3701, Flumann, Ruth, Childs, Dorothee, Childs, Liam ORCID: 0000-0002-2080-1804, Gaetjens-Sanchez, Ana-Maria, Bullinger, Lars ORCID: 0000-0002-5890-5510, Rosenwald, Andreas, Reinhardt, Hans Christian and Schmitt, Clemens A. ORCID: 0000-0002-4731-2226 (2021). Adaptive T-cell immunity controls senescence-prone MyD88-or CARD11-mutant B-cell lymphomas. Blood, 137 (20). S. 2785 - 2800. WASHINGTON: AMER SOC HEMATOLOGY. ISSN 1528-0020

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Abstract

Aberrant B-cell receptor/NF-kB signaling is a hallmark feature of B-cell non-Hodgkin lymphomas, especially in diffuse large B-cell lymphoma (DLBCL). Recurrent mutations in this cascade, for example, in CD79B, CARD11, or NFKBIZ, and also in the Toll-like receptor pathway transducer MyD88, all deregulate NF-kB, but their differential impact on lym-phoma development and biology remains to be determined. Here, we functionally investigate primary mouse lymphomas that formed in recipient mice of Emmyc transgenic hematopoietic stem cells stably transduced with naturally occurring NF-kappa B mutants. Although most mutants supported Myc-driven lymphoma formation through repressed apoptosis, CARD11-or MyD88-mutant lymphoma cells selectively presented with a macrophage-activating secretion profile, which, in turn, strongly enforced transforming growth factor beta (TGF-beta)-mediated senescence in the lymphoma cell compartment. How-ever, MyD88- or CARD11-mutant Em-myc lymphomas exhibited high-level expression of the immune-checkpoint mediator programmed cell death ligand 1 (PD-L1), thus preventing their efficient clearance by adaptive host immunity. Conversely, these mutant-specific dependencies were therapeutically exploitable by anti-programmed cell death 1 check-point blockade, leading to direct T-cell-mediated lysis of predominantly but not exclusively senescent lymphoma cells. Importantly, mouse-based mutant MyD88- and CARD11-derived signatures marked DLBCL subgroups exhibiting mirroring phenotypes with respect to the triad of senescence induction, macrophage attraction, and evasion of cytotoxic T-cell immunity. Complementing genomic subclassification approaches, our functional, cross-species investigation unveils pathogenic principles and therapeutic vulnerabilities applicable to and testable in human DLBCL subsets that may inform future personalized treatment strategies.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Reimann, MauriceUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schrezenmeier, JensUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Richter-Pechanska, PaulinaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Dolnik, AnnaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hick, Timon PabloUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schleich, KoljaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Cai, XiurongUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Fan, Dorothy N. Y.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lohneis, PhilippUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Masswig, SvenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Denker, SophyUNSPECIFIEDorcid.org/0000-0002-0736-6019UNSPECIFIED
Busse, AntoniaUNSPECIFIEDorcid.org/0000-0002-3470-6947UNSPECIFIED
Knittel, GeroUNSPECIFIEDorcid.org/0000-0001-8395-3701UNSPECIFIED
Flumann, RuthUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Childs, DorotheeUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Childs, LiamUNSPECIFIEDorcid.org/0000-0002-2080-1804UNSPECIFIED
Gaetjens-Sanchez, Ana-MariaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bullinger, LarsUNSPECIFIEDorcid.org/0000-0002-5890-5510UNSPECIFIED
Rosenwald, AndreasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Reinhardt, Hans ChristianUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schmitt, Clemens A.UNSPECIFIEDorcid.org/0000-0002-4731-2226UNSPECIFIED
URN: urn:nbn:de:hbz:38-601537
DOI: 10.1182/blood.2020005244
Journal or Publication Title: Blood
Volume: 137
Number: 20
Page Range: S. 2785 - 2800
Date: 2021
Publisher: AMER SOC HEMATOLOGY
Place of Publication: WASHINGTON
ISSN: 1528-0020
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
NF-KAPPA-B; ONCOGENE-INDUCED SENESCENCE; SOMATIC MUTATIONS; DISTINCT TYPES; CANCER MODELS; MOUSE; PATHOGENESIS; EXPRESSION; PROMOTES; GENESMultiple languages
HematologyMultiple languages
URI: http://kups.ub.uni-koeln.de/id/eprint/60153

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