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Genetic events underlying pathogenesis of nodal and extranodal marginal zone lymphoma are not completely understood. We report here a novel t(X;14)(p11.4;q32.33) identified in 4 lymphoma cases: 2 with a mucosa-associated lymphoid tissue lymphoma, one with a nodal marginal zone lymphoma and one with gastric diffuse large B-cell lymphoma. In all case...
Citations
... The activation of the G Protein-Coupled Receptor 34 (GPR34) through the phospholipase A1 (PLA1) pathway in lymphoepithelial lesions may promote B-cell survival and proliferation [101,102]. GPR34 translocations and mutations are specifically associated with SG MALT lymphoma [103,104]. It has therefore been proposed that GPR34 activation might constitute a link between LELs and SG MALT lymphomagenesis. ...
Among other systemic autoimmune diseases, primary Sjögren syndrome (pSS) bears the highest risk for lymphoma development. In pSS, chronic antigenic stimulation gradually drives the evolution from polyclonal B-cell expansion to oligoclonal/monoclonal B-cell predominance to malignant B-cell transformation. Thus, most pSS-related lymphomas are B-cell non-Hodgkin lymphomas (NHLs), with mucosa-associated lymphoid tissue (MALT) lymphomas predominating, followed by diffuse large B-cell lymphomas (DLBCLs) and nodal marginal zone lymphomas (NMZLs). Since lymphomagenesis is one of the most serious complications of pSS, affecting patients’ survival, a plethora of possible predisposing factors has been studied over the years, ranging from classical clinical, serological, hematological, and histological, to the more recently proposed genetic and molecular, allowing clinicians to timely detect and to closely follow-up the subgroup of pSS patients with increased risk for lymphoma development. Overall predisposing factors for pSS-related lymphomagenesis reflect the status of B-cell hyperactivity. Different clinical features have been described for each of the distinct pSS-related B-cell NHL subtypes. While generally pSS patients developing B-cell NHLs display a fairly good prognosis, outcomes in terms of treatment response and survival rates seem to differ depending on the lymphoma subtype, with MALT lymphomas being characterized by a rather indolent course and DLBCLs gravely affecting patients’ survival.
... G-protein coupled receptor 34 (GPR34) is a 7-transmembrane receptor that regulates key biological functions including cellular growth, motility, apoptosis, and gene transcription, and also appears to be involved in the progression of several cancers [1][2][3][4][5][6][7][8][9]. Several studies have addressed elevated expression levels of GPR34 in malignancies, including cervical cancer [7], metastatic melanoma [6], MALT lymphoma [1,2], BCR/ABL-positive leukemia [9], gastric cancer [5,8], and colon cancer [4], as well as its essential roles in tumor development and progression. ...
... G-protein coupled receptor 34 (GPR34) is a 7-transmembrane receptor that regulates key biological functions including cellular growth, motility, apoptosis, and gene transcription, and also appears to be involved in the progression of several cancers [1][2][3][4][5][6][7][8][9]. Several studies have addressed elevated expression levels of GPR34 in malignancies, including cervical cancer [7], metastatic melanoma [6], MALT lymphoma [1,2], BCR/ABL-positive leukemia [9], gastric cancer [5,8], and colon cancer [4], as well as its essential roles in tumor development and progression. Overexpression of GPR34 in lymphoma and HeLa cells results in phosphorylation of ERK, PKC, and CREB; induces CRE, AP1, and NF-κB-mediated gene transcription; and increases cell proliferation [1]. ...
... GPR34 upregulation has been detected in various tumor tissues, including melanoma [6], human MZL cells [1,2], leukemia [9], stomach [5,8], and cervical cancer [7]. Overexpression of GPR34 in lymphoma resulted in phosphorylation of ERK, induced NF-κB-mediated gene transcription, and increased cell proliferation [1]. ...
Purpose
G-protein coupled receptor (GPR 34) has been found to play important roles in some cancers and regulates the proliferation, apoptosis, and migration of these cancer cells. However, the mechanisms underlying how GPR34 functions to regulate growth and proliferation of colorectal cancer cells remains to be clarified.
Methods
We employed stable GPR34 knockdown LS174T cell models, GPR34 Mab blocking, a CCK-8 kit, and a colony formation assay to characterize the effect of GPR34 on the proliferation of LS174T in vitro and xenograft tumor growth in vivo. The mRNA level of GPR34 was detected by RT-PCR in tumor tissues and adjacent normal tissues from 34 CRC patients.
Results
Based on RT-PCR results, GPR34 exhibited high level in tumor samples compared with adjacent normal samples. Increased expression of GPR34 is more associated with poor prognosis of CRC as shown in The Cancer Genome Atlas (TCGA) dataset by Kaplan–Meier survival analysis. Furthermore, we showed that GPR34 knockdown inhibited the proliferation of LS174T colon cancer cells and related xenograft tumor growth. Searching for the distinct molecular mechanism, we identified several contributors to proliferation of LS174T colon cancer cells: PI3K subunits/PTEN, PDK1/AKT, and Src/Raf/Ras/ERK. GPR34 knockdown inhibited the proliferation of LS174T cells by upregulating expression of PTEN, and downregulating expression of PI3K subunits p110-beta.
Conclusion
Our findings provide direct evidence that GPR34 regulates the proliferation of LS174T cells and the growth of LS174T tumor xenografts by regulating different pathways. High expression of GPR34 mRNA could then be used to predict poor prognosis of CRC.
... Several novel chromosome translocations in occasional cases of MALT lymphoma have been described: t(3;14)(p13;q32)/FOXP1-IGH [118][119][120], t(1;14)(p21;q32)/CNN3-IGH, t(5;14)(q34;q32)/ODZ2-IGH, t(9;14)(p24;q32)/JMJD2C-IGH [121], t(X;14)(p11.4;q32)/GPR34-IGH [122,123] and t(1;2)(p22;p12) [103,124]. These translocations typically juxtapose the oncogene involved to the IGH gene locus, (or with the kappa light chain gene) and cause their over-expression. ...
... Furthermore, t(X;14)(p11.4;q32) which cause GPR34 over-expression is also restricted to MALT lymphoma of salivary gland, such as MALT lymphomas with GPR34 mutation [122,123]. ...
Simple Summary
Mucosa-associated lymphoid tissue (MALT) lymphoma is the most common subtype of marginal zone lymphomas. These B-cell neoplasms may arise from many organs and usually have an indolent behavior. Recurrent chromosomal translocations and cytogenetic alterations are well characterized, some of them being associated to specific sites. Through next-generation sequencing technologies, the mutational landscape of MALT lymphomas has been explored and available data to date show that there are considerable variations in the incidence and spectrum of mutations among MALT lymphoma of different sites. Interestingly, most of these mutations affect several common pathways and some of them are potentially targetable. Gene expression profile and epigenetic studies have also added new information, potentially useful for diagnosis and treatment. This article provides a comprehensive review of the genetic landscape in MALT lymphomas.
Abstract
Mucosa-associated lymphoid tissue (MALT) lymphomas are a diverse group of lymphoid neoplasms with B-cell origin, occurring in adult patients and usually having an indolent clinical behavior. These lymphomas may arise in different anatomic locations, sharing many clinicopathological characteristics, but also having substantial variances in the aetiology and genetic alterations. Chromosomal translocations are recurrent in MALT lymphomas with different prevalence among different sites, being the 4 most common: t(11;18)(q21;q21), t(1;14)(p22;q32), t(14;18)(q32;q21), and t(3;14)(p14.1;q32). Several chromosomal numerical abnormalities have also been described, but probably represent secondary genetic events. The mutational landscape of MALT lymphomas is wide, and the most frequent mutations are: TNFAIP3, CREBBP, KMT2C, TET2, SPEN, KMT2D, LRP1B, PRDM1, EP300, TNFRSF14, NOTCH1/NOTCH2, and B2M, but many other genes may be involved. Similar to chromosomal translocations, certain mutations are enriched in specific lymphoma types. In the same line, variation in immunoglobulin gene usage is recognized among MALT lymphoma of different anatomic locations. In the last decade, several studies have analyzed the role of microRNA, transcriptomics and epigenetic alterations, further improving our knowledge about the pathogenic mechanisms in MALT lymphoma development. All these advances open the possibility of targeted directed treatment and push forward the concept of precision medicine in MALT lymphomas.
... Several groups have implicated the role of LPS 1 in cancer. Several types of cancer, including colorectal cancer [47], cervical cancer [48], marginal zone lymphomas [49,50], and Bcr-Abl-transformed leukemia cells [51], highly express LPS 1 . In a cervical cancer cell line, downregulation of microRNA-381, which targets 3′-UTR of LPS 1 to suppress its expression, enhanced the expression of LPS 1 [48]. ...
Lysophosphatidylserine (LysoPS) is an emerging lysophospholipid (LPL) mediator, which acts through G protein-coupled receptors, like lysophosphatidic acid (LPA) and sphingosine 1-phosphate (S1P). LysoPS is detected in various tissues and cells and thought to be produced mainly by the deacylation of phosphatidylserine. LysoPS has been known to stimulate degranulation of mast cells. Recently, four LysoPS-specific G protein-coupled receptors (GPCRs) were identified. These GPCRs belong to the P2Y family which covers receptors for nucleotides and LPLs and are predominantly expressed in immune cells such as lymphocytes and macrophages. Studies on knockout mice of these GPCRs have revealed that LysoPS has immune-modulatory functions. Up-regulation of a LysoPS-producing enzyme, PS-specific phospholipase A 1 , was frequently observed in situations where the immune system is activated including autoimmune diseases and organ transplantations. Therefore, modulation of LysoPS signaling appears to be a promising method for providing therapies for the treatment of immune diseases. In this review, we summarize the biology of LysoPS-producing enzymes and receptors, recent developments in LysoPS signal modulators, and prospects for future therapeutic applications.
... Genetically, salivary gland MALT lymphoma exhibits a mutation profile distinct from other MALT lymphomas, featured by recurrent GPR34 translocation or mutations. [7][8][9][10] GPR34 is involved by t(X;14)(p11;q32), which juxtaposes GPR34 to the IG heavy chain enhancer region, thus causing its overexpression. [7][8][9] Thus far, the translocation has been found only in salivary gland MALT lymphoma, occurring in 3% of cases. ...
... [7][8][9][10] GPR34 is involved by t(X;14)(p11;q32), which juxtaposes GPR34 to the IG heavy chain enhancer region, thus causing its overexpression. [7][8][9] Thus far, the translocation has been found only in salivary gland MALT lymphoma, occurring in 3% of cases. Similarly, GPR34 mutations are almost exclusively seen in salivary gland MALT lymphoma but are more frequent, occurring in 16% of cases. ...
... This elegantly explains why the emergence of clonal malignant B cells is first seen around LELs and also why the GPR34 mutation and translocation are preferentially associated with salivary gland MALT lymphoma, as the full oncogenic potential of these genetic changes still depends on active receptor stimulation. [7][8][9][10] In keeping with this notion, both PLA1 and PLA2 activities are highly elevated in sera of patients with systemic lupus erythematosus and Sj€ ogren's syndrome, particularly in those with active disease. 28,29 The B-cell receptor expressed by most if not all salivary gland MALT lymphomas is autoreactive, with the majority bearing rheumatoid factor-like activities. ...
GPR34 translocation and mutation are specifically associated with salivary gland MALT lymphoma (SG-MALT-Lymphoma). Majority of GPR34 mutations are clustered in its C-terminus, resulting in truncated proteins lacking the phosphorylation motif important for receptor desensitization. It is unclear why GPR34 genetic changes associate with SG-MALT-Lymphoma and how these mutations contribute to the lymphoma development. We generated isogenic Flp-InTRex293 cell lines that stably expressed a single copy of GPR34 or its various mutants, and performed a range of in vitro assays. We showed that the GPR34 Q340X truncation, but not R84H and D151A mutants conferred a significantly increased resistance to apoptosis, and greater transforming potential than the GPR34 wild type. The GPR34 truncation mutant had a significantly delayed internalization than the wild type following ligand (lysophosphatidylserine) stimulation. Among 9 signaling pathways examined, the GPR34 Q340X truncation, to a lesser extent the D151A mutant, significantly activated CRE, NFkB and AP1 reporter activities, particularly in the presence of ligand stimulation. We further demonstrated enhanced activities of phospholipase-A1/2 in the culture supernatant of Flp-InTRex293 cells that expressed the GPR34 Q340X mutant, and their potential to catalyze the synthesis of lysophosphatidylserine from phosphatidylserine. Importantly, phospholipase-A1 was abundantly expressed in the duct epithelium of salivary glands and those involved in lymphoepithelial lesions (LELs). Our findings advocate a model of paracrine stimulation of malignant B-cells via GPR34, in which PLA is released by LELs, and hydrolyzes the phosphatidylserine exposed on apoptotic cells, generating lysophosphatidylserine, the ligand for GPR34. Thus, GPR34 activation potentially bridges LELs to genesis of SG-MALT-Lymphoma.
... has been frequently associated with cancer. As a consequence of this fusion, upregulation of GPR34 mRNA and aberrant expression of GPR34 was found in mucosa-associated lymphoid tissue lymphoma (Ansell et al., 2012;Baens et al., 2012;Akasaka et al., 2017). Here, the G i proteincoupled GPR34 most probably drives cell proliferation by activating the mitogen-activated protein kinase pathway because of immunoglobulin heavy chain locus-driven high expression and the receptors' high basal activity (Schöneberg et al., 2018). ...
There are approximately 800 annotated
G protein–coupled receptor (GPCR) genes, making
these membrane receptors members of the most abundant
gene family in the human genome. Besides being
involved in manifold physiologic functions and serving
as important pharmacotherapeutic targets, mutations
in 55 GPCR genes cause about 66 inherited monogenic
diseases in humans. Alterations of nineGPCRgenes are
causatively involved in inherited digenic diseases. In
addition to classic gain- and loss-of-function variants,
other aspects, such as biased signaling, trans-signaling,
ectopic expression, allele variants ofGPCRs, pseudogenes,
gene fusion, andgene dosage, contribute to the repertoire
of GPCR dysfunctions. However, the spectrum of
alterations and GPCR involvement is probably much
larger because an additional 91 GPCR genes contain
homozygous or hemizygous loss-of-function mutations
in human individuals with currently unidentified
phenotypes. This review highlights the complexity
of genomic alteration of GPCR genes as well as
their functional consequences and discusses derived
therapeutic approaches.
... GPR34 is a G-protein coupled receptor (GPCR) and is deregulated by t(X:14)(p11.4;q32) in MALT lymphoma of salivary gland and lung with a history of Sjögren syndrome. 20,22,23 In view of this finding, we screened salivary gland MALT lymphoma for t(X;14)(p11;q32) by interphase FISH, and identified the translocation in 2 of 58 (3%) cases (Online Supplementary Figure S4). Interestingly, GPR34 mutation and translocation were mutually exclusive, together seen in 11 of 58 (19%) cases of salivary gland MALT lymphoma (Figure 1 and Online Supple mentary Figure S4). ...
MALT lymphoma originates from a background of diverse chronic inflammatory disorders at various anatomic sites. The genetics underlying its development, particularly in those associated with autoimmune disorders, is poorly characterised. By whole exome sequencing of 21 cases of MALT lymphomas of the salivary gland and thyroid, we have identified recurrent somatic mutations in 2 G-protein coupled receptors (GPR34 and CCR6) not previously reported in human malignancies, 3 genes (PIK3CD, TET2, TNFRSF14) not previously implicated in MALT lymphoma, and a further 2 genes (TBL1XR1, NOTCH1) recently described in MALT lymphoma. The majority of mutations in GPR34 and CCR6 were nonsense and frameshift changes clustered in the C-terminal cytoplasmic tail, and would result in truncated proteins that lack the phosphorylation motif important for β-arrestin mediated receptor desensitization and internalisation. Screening of these newly identified mutations, together with previously identified genetic changes, identified distinct mutation profiles in MALT lymphoma of various sites, with those of salivary gland characterised by frequent TBL1XR1 and GPR34 mutations, thyroid by frequent TET2, TNFRSF14 and PIK3CD mutations, and ocular adnexa by frequent TNFAIP3 mutation. Interestingly, in MALT lymphoma of the salivary gland, there was a significant positive association between TBL1XR1 mutation and GPR34 mutation/translocation (P=0.0002). In those of ocular adnexa, TBL1XR1 mutation was mutually exclusive from TNFAIP3 mutation (P=0.049), but significantly associated with IGHV3-23 usage (P=0.03) and PIK3CD mutation (P=0.009). These findings unravel novel insights into the molecular mechanisms of MALT lymphoma and provide further evidence for potential oncogenic cooperation between receptor signalling and genetic changes.
... Occasionally, chromosomal translocations and gene amplifications involving transcription factor BCL6 on 3q27.3 have been described in EMZL [76]. Other rare translocations involving IGH in EMZL include t(X;14)(p11;q32)/IGH-GPR34 [77,78], t(5;14)(q34;q32)/IGH-TENM2, and t(9;14)(p24;q32)/IGH-KDM4C [79]. GPR34 encodes an orphan G protein-coupled receptor highly expressed in immune cells, while TENM2 represents a teneurin transmembrane protein regulating cell-cell contact. ...
Extranodal marginal zone lymphoma (EMZL), mostly represented by mucosa-associated lymphoid tissue (MALT) type, also referred to as MALT lymphoma, is a clinically heterogeneous entity within the group of low-grade B cell lymphomas that arises in a wide range of different extranodal sites, including the stomach, lung, ocular adnexa, and skin. It represents the third most common non-Hodgkin lymphoma in the Western world, and the median age of occurrence is around 60 years. One characteristic aspect in a subset of EMZL detectable in about 25% of the cases is the presence of specific chromosomal translocations involving the genes MALT1 and BCL10, which lead to activation of the NF-κB signaling pathway. Another unique aspect is that several infectious agents, such as Helicobacter pylori in the case of gastric EMZL, and autoimmune disorders, like Sjögren syndrome, have been implicated in the pathogenesis of this cancer. Recent findings as summarized in this review have further improved our understanding of the complex pathobiology of this disease and have been essential to better define novel treatment strategies. In addition, many of these specific features are currently being implemented for the diagnosis of EMZL.
... There are also several novel chromosome translocations including t(3;14)(p13;q32)/FOXP1-IGH [133][134][135], t(1;14)(p21;q32)/CNN3-IGH, t(5;14)(q34;q32)/ODZ2-IGH, t(9;14)(p24;q32)/JMJD2C-IGH [136] and t(X;14)(p11.4;q32)/GPR34-IGH [137,138], which are reported in isolated cases of MALT lymphoma. These translocations are predicted to cause over-expression of the oncogene involved as these are in association with the IGH gene locus, thus under the transcriptional control of the IG gene enhancer. ...
Extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma) invariably arises from a background of chronic microbial infection and/or autoimmune disorder at diverse mucosal sites. The prolonged chronic infection and/or autoimmunity generate active immune and inflammatory responses that provide a setting for evolution and development of autoreactive B-cells, their expansion and eventual malignant transformation following acquisition of genetic changes. The immune responses also play a critical role in sustaining the growth and survival of the transformed cells as shown by complete regression of a high proportion of MALT lymphoma of the stomach, ocular adnexa and skin following anti-microbial treatment. B-cell receptor engagement by auto-antigen as well as T-cell help including both cognate interaction and bystander help via soluble ligands such as CD40L and BAFF are thought to underpin the immunological drive in the lymphoma development through activation of the canonical and non-canonical NF-κB pathway respectively. Similarly, the three MALT lymphoma associated chromosome translocations, namely t(1;14)(p22;q32)/$\textit{BCL10-IGH}$, t(14;18)(q32;q21)/$\textit{IGH-MALT1}$, and t(11;18)(q21;q21)/$\textit{BIRC3}$ ($\textit{API2}$)$\textit{-MALT1}$, are also capable of activating both canonical and non-canonical NF-κB pathways. Furthermore, $\textit{TNFAIP3}$ (A20) inactivation by deletion and/or mutation abolishes the auto-negative feedback to several signalling including BCR and TLR, which connect to the canonical NF-κB activation pathway. Thus, there is a considerable overlap in the molecular pathways dysregulated by immunological drive and somatic genetic changes, strongly arguing for their oncogenic cooperation in the development of MALT lymphoma.
... GPR34 belongs to the P2Y 12 -like receptor group, and its expression levels have been related to impaired immunity (6,11) and development of lymphoma and gastric cancer (35)(36)(37)(38). Upregulation of the receptor has also been linked to neuroinflammation (9). ...
Dendritic cells (DCs) are specifically equipped with the G protein-coupled receptor 34 (GPR34). Tight regulation of GPR34 gene expression seems highly important for proper immunological functions, because the absence of this receptor leads to an alteration of the immune response, whereas overexpression was reported to be involved in neuroinflammation. However, the regulatory mechanism of GPR34 expression has not yet been investigated. Whole-transcriptome RNA sequencing analysis from spleens and DCs of GPR34 knockout and wild-type mice, combined with protein-protein interaction data, revealed functional modules affected by the absence of this receptor. Among these, NF-κB, MAPK, and apoptosis-signaling pathways showed high significance. Using murine DCs we experimentally show that NF-κB and MAPK pathways are involved in the downregulation of GPR34. DCs lacking GPR34 have a higher caspase-3/7 activity and increased apoptosis levels. Our study reveals a novel role of GPR34 in the fate of DCs and identifies a regulatory mechanism that could be relevant for treatment of GPR34-overexpressing pathologies, such as neuroinflammatory or cancer conditions.
