Universität zu Köln

Montesinos-Rongen, Manuel, Brunn, Anna, Sanchez-Ruiz, Monica, Kueppers, Ralf, Siebert, Reiner and Deckert, Martina (2021). Impact of a Faulty Germinal Center Reaction on the Pathogenesis of Primary Diffuse Large B Cell Lymphoma of the Central Nervous System. Cancers, 13 (24). BASEL: MDPI. ISSN 2072-6694

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Abstract

Simple Summary The pathogenetic mechanisms and peculiar tropism of primary CNS lymphoma (PCNSL) of the central nervous system (CNS) have been the subject of debate for decades. Hypothesis-driven targeted molecular studies have revealed that PCNSLs derived from self-/polyreactive B cells that have escaped developmental control mechanisms. The early acquisition of activating mutations targeting the B cell receptor pathway provides a survival advantage. The failure of the germinal center (GC) reaction and its checkpoints increases tumor B cell affinity for the CNS. During this faulty GC reaction, PCNSL tumor cells acquire further oncogenic alterations converging on the Toll-like receptor, B cell receptor, and NF-kappa B pathway. These activated pathways sustain proliferation. Concomitantly, cells become unable to complete terminal B cell differentiation, becoming trapped within the vicious cycle of the GC reaction as low-affinity IgM+ B cells related to memory cells. Primary lymphoma of the central nervous system (PCNSL, CNS) is a specific diffuse large B cell lymphoma (DLBCL) entity confined to the CNS. Key to its pathogenesis is a failure of B cell differentiation and a lack of appropriate control at differentiation stages before entrance and within the germinal center (GC). Self-/polyreactive B cells rescued from apoptosis by MYD88 and/or CD79B mutations accumulate a high load of somatic mutations in their rearranged immunoglobulin (IG) genes, with ongoing somatic hypermutation (SHM). Furthermore, the targeting of oncogenes by aberrant SHM (e.g., PIM1, PAX5, RHOH, MYC, BTG2, KLHL14, SUSD2), translocations of the IG and BCL6 genes, and genomic instability (e.g., gains of 18q21; losses of 9p21, 8q12, 6q21) occur in these cells in the course of their malignant transformation. Activated Toll-like receptor, B cell receptor (BCR), and NF-kappa B signaling pathways foster lymphoma cell proliferation. Hence, tumor cells are arrested in a late B cell differentiation stage, corresponding to late GC exit B cells, which are genetically related to IgM+ memory cells. Paradoxically, the GC reaction increases self-/polyreactivity, yielding increased tumor BCR reactivity for multiple CNS proteins, which likely contributes to CNS tropism of the lymphoma. The loss of MHC class I antigen expression supports tumor cell immune escape. Thus, specific and unique interactions of the tumor cells with resident CNS cells determine the hallmarks of PCNSL.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Montesinos-Rongen, Manuel UNSPECIFIED UNSPECIFIED UNSPECIFIED Brunn, Anna UNSPECIFIED UNSPECIFIED UNSPECIFIED Sanchez-Ruiz, Monica UNSPECIFIED UNSPECIFIED UNSPECIFIED Kueppers, Ralf UNSPECIFIED UNSPECIFIED UNSPECIFIED Siebert, Reiner UNSPECIFIED UNSPECIFIED UNSPECIFIED Deckert, Martina UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-580007
DOI:	10.3390/cancers13246334
Journal or Publication Title:	Cancers
Volume:	13
Number:	24
Date:	2021
Publisher:	MDPI
Place of Publication:	BASEL
ISSN:	2072-6694
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language PRIMARY CNS LYMPHOMA; GENE-EXPRESSION; CHROMOSOMAL TRANSLOCATIONS; CLASS SWITCH; HLA REGION; BCL6; RECURRENT; MUTATIONS; FEATURES; PATTERN Multiple languages Oncology Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/58000