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Novel insights into the molecular pathogenesis of gastric MALT lymphoma


Craig, V J. Novel insights into the molecular pathogenesis of gastric MALT lymphoma. 2010, University of Zurich, Faculty of Science.

Abstract

Gastric marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue
(MALT lymphoma) represents a distinct class of extranodal lymphoma that evolves against a
background of chronic inflammation induced by persistent infection with the bacterium
Helicobacter pylori. In its early stages, MALT lymphoma is an antigen-dependent disease
characterised by an indolent clinical course and in most cases is treatable by antibiotic
eradication therapy alone. Low grade MALT lymphomas can eventually undergo high grade
transformation to a more aggressive counterpart termed gastric diffuse large B-cell
lymphoma (gDLBCL). At this stage the lymphomas grow autonomously and are refractory to
Helicobacter eradication therapy. Little is known about the molecular mechanisms governing
the development of low grade MALT lymphoma and its ultimate progression to gDLBCL.
To improve our current understanding of the molecular pathogenesis of MALT lymphoma, a
multidimensional approach was taken to investigate various aspects of this disease during the
course of my PhD thesis.
Although a variety of circumstantial evidence has implicated an important role for
antigen in MALT lymphomagenesis, the identity of such ligands recognised by the tumour
cells remain unclear. To address this issue of antigen-receptor specificity, enzyme
immunoassays were employed to systematically analyse the antigen binding profile of a
comprehensive panel of human and murine recombinant MALT lymphoma-derived
antibodies. The majority of tumour derived immunoglobulins were found to exhibit a broad
reactivity profile in line with the definition of polyreactivity. In addition, using the BALB/c
mouse model of Helicobacter-induced gastric MALT lymphoma, we demonstrated that
explanted tumour cells proliferated in response to a variety of cognate antigens recognised by
their polyreactive B-cell receptor. Our results therefore suggest that MALT lymphoma
development may be facilitated by an array of local self- and foreign antigens, providing
direct antigenic stimulation of the tumour cells via their B-cell receptor.
A characteristic feature of gastric MALT lymphomas is that they are typically
infiltrated by large numbers of T-helper cells producing interleukin-4 (IL4) and other Thelper cell type 2 cytokines. Therefore, an additional aim of this study was to elucidate the
pathogenic role of the tumour-infiltrating T-cell population. Tumour cell proliferation was
strongly enhanced by the presence of intratumoural CD4+ T cells in a CD40/CD40Lindependent
manner. Another key finding was that a substantial fraction of tumourinfiltrating
CD4+ T cells were functional CD25+FoxP3+ regulatory T (Treg) cells. These cells
were found to be recruited by the tumour cells themselves through secretion of the Tregattracting
chemokines CCL17 and CCL22. Interestingly, the depletion of CD25+ T cells was
as efficient as CD4+ T-cell depletion in blocking tumour growth ex vivo and in vivo. Judging
from our data, we propose that MALT lymphoma cells require at least two independent
signals for proliferation. One signal is received by the functional surface-bound polyreactive
immunoglobulin, while the other signal is delivered by tumour-infiltrating T cells, in
particular by Tregs, which are likely to play a direct role in stimulating tumour growth.
To date, MALT lymphoma research has largely focused on altered expression of
protein coding genes. However, recent evidence suggests that alterations of non-coding
RNA, particularly microRNA (miRNA), also contribute to tumourigenesis. Using a genomewide
microarray-based approach, we defined the unique miRNA expression signature
associated with the development and progression of this disease. A special focus was first
laid upon miR-203 and its putative tumour suppressive function during the progression from
reactive Helicobacter-specific gastritis to MALT lymphoma. We identified miR-203 to be
significantly downregulated in MALT lymphoma tissue due to hypermethylation of the miR-
203 locus. The restoration of miR-203 expression in primary MALT lymphoma cells
repressed the recently identified miR-203 target, ABL1, and blocked tumour cell
proliferation. Finally, pharmacological inhibition of ABL1 activity by imatinib blocked
MALT lymphoma cell proliferation ex vivo and effectively eradicated tumours in vivo.
Collectively, our observations suggest that ABL1 plays an important role in MALT
lymphoma cell biology and support a novel potential application of imatinib in the treatment
of MALT lymphoma.
Our genome-wide survey further revealed a characteristic set of MYC-repressed
miRNAs to be specifically downregulated in human gDLBCL compared to MALT lymphoma and gastritis. Aberrant MYC expression indeed correlated with high grade
transformation as evident from our tissue microarray analysis. The re-expression of a panel
of selected MYC-associated miRNAs significantly reduced the proliferation of DLBCL cells.
In particular, miR-34a was found to represent the most potent tumour suppressor in DLBCL
cell lines. We could further attribute the tumour suppressive effects of miR-34a to
dysregulation of its target FOXP1. Accordingly, FOXP1 overexpression was found to be
strongly associated with gDLBCL and the transient knockdown of FOXP1 in DLBCL cell
lines significantly impaired the proliferation of the tumour cells. Taken together, our findings
elucidate a novel mechanism linking the aberrant expression of MYC and concomitant
repression of miR-34a to FOXP1 deregulation in high grade transformation of MALT
lymphoma.

Abstract

Gastric marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue
(MALT lymphoma) represents a distinct class of extranodal lymphoma that evolves against a
background of chronic inflammation induced by persistent infection with the bacterium
Helicobacter pylori. In its early stages, MALT lymphoma is an antigen-dependent disease
characterised by an indolent clinical course and in most cases is treatable by antibiotic
eradication therapy alone. Low grade MALT lymphomas can eventually undergo high grade
transformation to a more aggressive counterpart termed gastric diffuse large B-cell
lymphoma (gDLBCL). At this stage the lymphomas grow autonomously and are refractory to
Helicobacter eradication therapy. Little is known about the molecular mechanisms governing
the development of low grade MALT lymphoma and its ultimate progression to gDLBCL.
To improve our current understanding of the molecular pathogenesis of MALT lymphoma, a
multidimensional approach was taken to investigate various aspects of this disease during the
course of my PhD thesis.
Although a variety of circumstantial evidence has implicated an important role for
antigen in MALT lymphomagenesis, the identity of such ligands recognised by the tumour
cells remain unclear. To address this issue of antigen-receptor specificity, enzyme
immunoassays were employed to systematically analyse the antigen binding profile of a
comprehensive panel of human and murine recombinant MALT lymphoma-derived
antibodies. The majority of tumour derived immunoglobulins were found to exhibit a broad
reactivity profile in line with the definition of polyreactivity. In addition, using the BALB/c
mouse model of Helicobacter-induced gastric MALT lymphoma, we demonstrated that
explanted tumour cells proliferated in response to a variety of cognate antigens recognised by
their polyreactive B-cell receptor. Our results therefore suggest that MALT lymphoma
development may be facilitated by an array of local self- and foreign antigens, providing
direct antigenic stimulation of the tumour cells via their B-cell receptor.
A characteristic feature of gastric MALT lymphomas is that they are typically
infiltrated by large numbers of T-helper cells producing interleukin-4 (IL4) and other Thelper cell type 2 cytokines. Therefore, an additional aim of this study was to elucidate the
pathogenic role of the tumour-infiltrating T-cell population. Tumour cell proliferation was
strongly enhanced by the presence of intratumoural CD4+ T cells in a CD40/CD40Lindependent
manner. Another key finding was that a substantial fraction of tumourinfiltrating
CD4+ T cells were functional CD25+FoxP3+ regulatory T (Treg) cells. These cells
were found to be recruited by the tumour cells themselves through secretion of the Tregattracting
chemokines CCL17 and CCL22. Interestingly, the depletion of CD25+ T cells was
as efficient as CD4+ T-cell depletion in blocking tumour growth ex vivo and in vivo. Judging
from our data, we propose that MALT lymphoma cells require at least two independent
signals for proliferation. One signal is received by the functional surface-bound polyreactive
immunoglobulin, while the other signal is delivered by tumour-infiltrating T cells, in
particular by Tregs, which are likely to play a direct role in stimulating tumour growth.
To date, MALT lymphoma research has largely focused on altered expression of
protein coding genes. However, recent evidence suggests that alterations of non-coding
RNA, particularly microRNA (miRNA), also contribute to tumourigenesis. Using a genomewide
microarray-based approach, we defined the unique miRNA expression signature
associated with the development and progression of this disease. A special focus was first
laid upon miR-203 and its putative tumour suppressive function during the progression from
reactive Helicobacter-specific gastritis to MALT lymphoma. We identified miR-203 to be
significantly downregulated in MALT lymphoma tissue due to hypermethylation of the miR-
203 locus. The restoration of miR-203 expression in primary MALT lymphoma cells
repressed the recently identified miR-203 target, ABL1, and blocked tumour cell
proliferation. Finally, pharmacological inhibition of ABL1 activity by imatinib blocked
MALT lymphoma cell proliferation ex vivo and effectively eradicated tumours in vivo.
Collectively, our observations suggest that ABL1 plays an important role in MALT
lymphoma cell biology and support a novel potential application of imatinib in the treatment
of MALT lymphoma.
Our genome-wide survey further revealed a characteristic set of MYC-repressed
miRNAs to be specifically downregulated in human gDLBCL compared to MALT lymphoma and gastritis. Aberrant MYC expression indeed correlated with high grade
transformation as evident from our tissue microarray analysis. The re-expression of a panel
of selected MYC-associated miRNAs significantly reduced the proliferation of DLBCL cells.
In particular, miR-34a was found to represent the most potent tumour suppressor in DLBCL
cell lines. We could further attribute the tumour suppressive effects of miR-34a to
dysregulation of its target FOXP1. Accordingly, FOXP1 overexpression was found to be
strongly associated with gDLBCL and the transient knockdown of FOXP1 in DLBCL cell
lines significantly impaired the proliferation of the tumour cells. Taken together, our findings
elucidate a novel mechanism linking the aberrant expression of MYC and concomitant
repression of miR-34a to FOXP1 deregulation in high grade transformation of MALT
lymphoma.

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Additional indexing

Item Type:Dissertation
Referees:Müller A, Cogliatti S, Nadal D, Renner C
Communities & Collections:04 Faculty of Medicine > Institute of Molecular Cancer Research
07 Faculty of Science > Institute of Molecular Cancer Research
Dewey Decimal Classification:570 Life sciences; biology
Language:English
Date:2010
Deposited On:31 Oct 2011 13:25
Last Modified:05 Apr 2016 15:03
Number of Pages:145
Related URLs:http://opac.nebis.ch/F/?local_base=NEBIS&con_lng=GER&func=find-b&find_code=SYS&request=006436063

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