Distinct signatures of B‐cell homeostatic and activation‐dependent chemokine receptors in the development and progression of extragastric MALT lymphomas

Deutsch, Alexander; Aigelsreiter, Ariane; Steinbauer, Elisabeth; Frühwirth, Martin; Kerl, Helmut; Beham‐Schmid, Christine; Schaider, Helmut; Neumeister, Peter

doi:10.1002/path.2372

Cited by 43 publications

(42 citation statements)

References 65 publications

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“…Some of these chemokine receptors have already been described in MALT lymphoma and in diffuse large B-cell lymphoma likewise by several authors. 9,11,16,[29][30][31] In our study, CCR9 mRNA expression significantly correlated with the proliferation rate in both lymphoma entities and its protein expression was restricted to malignant B cells with a significantly higher occurrence on extranodal diffuse large B-cell lymphoma cells. Expression of CCR9 was described to be localized on gut-homing B and T cells having a role in mucosal immune response.…”

Section: Discussionmentioning

confidence: 99%

“…A similar upregulation of CCR1 and CCR5 during the transformation process of extragastric MALT lymphoma was recently reported by us. 16 CCR8 and XCR1 expression has not yet been described in gastric extranodal diffuse large B-cell lymphoma so far. As CCR8 mediates rescue from steroid-induced apoptosis via an ERK-dependent pathway, it is conceivable that anti-apoptotic effects may contribute to high-grade transformation.…”

Section: Discussionmentioning

confidence: 99%

“…Scoring of tissue slides and determination of the immunoreactive score (IRS) was performed as previously described by our group. 16 …”

Section: Immunohistochemical Analyses For Ccr1 Ccr5 Cxcr6 and Xcr1mentioning

confidence: 99%

“…15,16 The real-time PCR and calculation of the expression levels were performed according to a protocol previously reported by Seidl et al 17 The nucleotide acid sequences for the primers and probes used for the determination of the expression levels of 19 chemokine receptors are shown in the Supplementary Table S1.…”

Section: Rna Isolation Cdna Synthesis and Real-time Pcrmentioning

confidence: 99%

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Chemokine receptors in gastric MALT lymphoma: loss of CXCR4 and upregulation of CXCR7 is associated with progression to diffuse large B-cell lymphoma

et al. 2013

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Chemokine receptors have a crucial role in the development and progression of lymphoid neoplasms. To determine the chemokine receptor expression profile in gastric mucosa-associated lymphoid tissue (MALT) lymphoma, we performed an expression analysis of 19 chemokine receptors at mRNA levels by using real-time RT-PCR, as well as of five chemokine receptors-CCR8, CCR9, CXCR4, CXCR6 and CXCR7-by immunohistochemistry on human tissue samples of Helicobacter pylori-associated gastritis, gastric MALT lymphoma and gastric extranodal diffuse large B-cell lymphoma originating from MALT lymphoma (transformed MALT lymphoma). Following malignant transformation from H. pylori-associated gastritis to MALT lymphoma, an upregulation of CCR7, CXCR3 and CXCR7, and a loss of CXCR4 were detected. The transformation of gastric MALT lymphomas to gastric extranodal diffuse large B-cell lymphoma was accompanied by upregulation of CCR1, CCR5, CCR7, CCR8, CCR9, CXCR3, CXCR6, CXCR7 and XCR1. Remarkably, CXCR4 expression was exclusively found in nodal marginal B-cell lymphomas and nodal diffuse large B-cell lymphomas but not at extranodal manifestation sites, ie, in gastric MALT lymphomas or gastric extranodal diffuse large B-cell lymphomas. Furthermore, the incidence of bone marrow infiltration (16/51 with bone marrow involvement vs 35/51 with bone marrow involvement; Spearman q ¼ 0467 Po0.001) positively correlated with CXCR4 expression. CXCL12, the ligand of CXCR4 and CXCR7, was expressed by epithelial, endothelial and inflammatory cells, MALT lymphoma cells and was most strongly expressed by extranodal diffuse large B-cell lymphoma cells, suggesting at least in part an autocrine signaling pathway. Our data indicate that CXCR4 expression is associated with nodal manifestation and a more advanced stage of lymphomas and hence, might serve as useful clinical prognostic marker.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

“…Scoring of tissue slides and determination of the immunoreactive score (IRS) was performed as previously described by our group. 16 …”

Section: Immunohistochemical Analyses For Ccr1 Ccr5 Cxcr6 and Xcr1mentioning

confidence: 99%

Section: Rna Isolation Cdna Synthesis and Real-time Pcrmentioning

confidence: 99%

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Chemokine receptors in gastric MALT lymphoma: loss of CXCR4 and upregulation of CXCR7 is associated with progression to diffuse large B-cell lymphoma

et al. 2013

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“…However, the molecular biology of lymphoma dissemination is incompletely understood and so far mainly based on clinical observations. Up until now, an important role in dissemination has been established for cell adhesion molecules (e.g., L-selectin and integrins), chemokine receptors, and chemokine ligands, which are also known to be involved in lymphocyte homing programs (39,(49)(50)(51). We show here in a genetically defined mouse model that p73 loss promotes extralymphatic dissemination of Myc-driven lymphoma and alters the transcriptional signature of the malignant B cells, including cell-surface-associated adhesion molecules, chemokine receptors, their ligands, and cluster of differentiation antigens.…”

Section: Discussionmentioning

confidence: 99%

Loss of p73 promotes dissemination of Myc-induced B cell lymphomas in mice

Nemajerová

Petrenko²,

Trümper³

et al. 2010

J. Clin. Invest.

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Mice engineered to express c-Myc in B cells (Eμ-myc mice) develop lethal lymphomas in which the gene encoding the p53 tumor suppressor is frequently mutated. Whether the p53 homolog p73 also functions as a tumor suppressor in vivo remains controversial. Here we have shown that p73 loss does not substantially affect disease onset and mortality in Eμ-myc mice. However, it does alter the phenotype of the disease. Specifically, p73 loss decreased nodal disease and increased widespread extranodal dissemination. We further found that p53 acted as the dominant tumor suppressor during the onset of Eμ-myc-driven B cell lymphomagenesis, while p73 modulated tumor dissemination and extranodal growth. Immunophenotyping and expression profiling suggested that p73 loss allowed increased maturation of malignant B cells and deregulated genes involved in lymphocyte homing and dissemination of human lymphomas. Consistent with this, p73 expression was frequently downregulated in a large cohort of human mature aggressive B cell lymphomas, and both the incidence and degree of p73 downregulation in these tumors correlated with their extranodal dissemination status. These data indicate that p73 is a modifier of Myc-driven lymphomas in mice, favoring tumor dissemination, and suggest that p73 could be a biomarker for human B cell lymphoma dissemination, a notion that can now be tested in clinicopathologic correlation studies.

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