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Critical influences on the pathogenesis of follicular lymphoma

Critical influences on the pathogenesis of follicular lymphoma
Critical influences on the pathogenesis of follicular lymphoma

The development of follicular lymphoma (FL) from a founder B cell with an upregulation of B-cell lymphoma 2 (BCL2), via the t(14;18) translocation, to a proliferating clone, poised to undergo further transformation to an aggressive lymphoma, illustrates the opportunistic Darwinian process of tumorigenesis. Protection against apoptosis allows an innocent cell to persist and divide, with dangerous accumulation of further mutational changes, commonly involving inactivation of chromatin-modifying genes. But this is not all. FL cells reflect normal B cells in relying on expression of surface immunoglobulin. In doing so, they add another supportive mechanism by exploiting the natural process of somatic hypermutation of the IGV genes. Positive selection of motifs for addition of glycan into the antigen-binding sites of virtually all cases, and the placement of unusual mannoses in those sites, reveals a posttranslational strategy to engage the microenvironment. A bridge between mannosylated surface immunoglobulin of FL cells and macrophage-expressed dendritic cell-specific ICAM-3-grabbing nonintegrin produces a persistent low-level signal that appears essential for life in the hostile germinal center. Early-stage FL therefore requires a triad of changes: protection from apoptosis, mutations in chromatin modifiers, and an ability to interact with lectin-expressing macrophages. These changes are common and persistent. Genetic/epigenetic analysis is providing important data but investigation of the posttranslational landscape is the next challenge. We have one glimpse of its operation via the influence of added glycan on the B-cell receptor of FL. The consequential interaction with environmental lectins illustrates how posttranslational modifications can be exploited by tumor cells, and could lead to new approaches to therapy.

Journal Article, Review
0006-4971
2297-2306
Küppers, Ralf
9ce6d145-0861-41b0-903c-2684bbfdd50c
Stevenson, Freda K
ba803747-c0ac-409f-a9c2-b61fde009f8c
Küppers, Ralf
9ce6d145-0861-41b0-903c-2684bbfdd50c
Stevenson, Freda K
ba803747-c0ac-409f-a9c2-b61fde009f8c

Küppers, Ralf and Stevenson, Freda K (2018) Critical influences on the pathogenesis of follicular lymphoma. Blood, 131 (21), 2297-2306. (doi:10.1182/blood-2017-11-764365).

Record type: Review

Abstract

The development of follicular lymphoma (FL) from a founder B cell with an upregulation of B-cell lymphoma 2 (BCL2), via the t(14;18) translocation, to a proliferating clone, poised to undergo further transformation to an aggressive lymphoma, illustrates the opportunistic Darwinian process of tumorigenesis. Protection against apoptosis allows an innocent cell to persist and divide, with dangerous accumulation of further mutational changes, commonly involving inactivation of chromatin-modifying genes. But this is not all. FL cells reflect normal B cells in relying on expression of surface immunoglobulin. In doing so, they add another supportive mechanism by exploiting the natural process of somatic hypermutation of the IGV genes. Positive selection of motifs for addition of glycan into the antigen-binding sites of virtually all cases, and the placement of unusual mannoses in those sites, reveals a posttranslational strategy to engage the microenvironment. A bridge between mannosylated surface immunoglobulin of FL cells and macrophage-expressed dendritic cell-specific ICAM-3-grabbing nonintegrin produces a persistent low-level signal that appears essential for life in the hostile germinal center. Early-stage FL therefore requires a triad of changes: protection from apoptosis, mutations in chromatin modifiers, and an ability to interact with lectin-expressing macrophages. These changes are common and persistent. Genetic/epigenetic analysis is providing important data but investigation of the posttranslational landscape is the next challenge. We have one glimpse of its operation via the influence of added glycan on the B-cell receptor of FL. The consequential interaction with environmental lectins illustrates how posttranslational modifications can be exploited by tumor cells, and could lead to new approaches to therapy.

Text
ASH-2018-MLB-Blood reviews-FSRK - Accepted Manuscript
Restricted to Repository staff only until 24 May 2019.
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More information

Accepted/In Press date: 28 December 2017
e-pub ahead of print date: 17 April 2018
Published date: 24 May 2018
Additional Information: © 2018 by The American Society of Hematology.
Keywords: Journal Article, Review

Identifiers

Local EPrints ID: 421843
URI: https://eprints.soton.ac.uk/id/eprint/421843
ISSN: 0006-4971
PURE UUID: 725925fb-1853-4452-9457-85ed4dd00749
ORCID for Freda K Stevenson: ORCID iD orcid.org/0000-0002-0933-5021

Catalogue record

Date deposited: 29 Jun 2018 16:30
Last modified: 14 Mar 2019 01:51

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