PLAG1-HAS2 fusion in lipoblastoma with masked 8q intrachromosomal rearrangement

Morerio, Cristina; Rapella, Annamaria; Rosanda, Cristina; Tassano, Elisa; Gambini, Claudio; Romagnoli, Giuseppe; Panarello, Claudio

doi:10.1016/j.cancergencyto.2004.04.017

Cited by 43 publications

(35 citation statements)

References 4 publications

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“…In addition to pleomorphic adenomas, ectopic expression of PLAG1 is also found in lipoblastomas (16)(17)(18), hepatoblastomas (19), and AML (20,21). The oncogenic capacity of PLAG1 has been demonstrated in vitro, i.e.…”

Section: Introductionmentioning

confidence: 93%

Upregulation of Igf and Wnt signalling associated genes in pleomorphic adenomas of the salivary glands in PLAG1 transgenic mice

Declercq

Dyck²,

Damme³

et al. 2008

Int J Oncol

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Abstract. The Pleomorphic adenoma gene 1 (PLAG1) is involved in various human neoplasias, including pleomorphic adenomas of the salivary glands. Moreover, the oncogenic role of PLAG1 was clearly demonstrated in two independent PLAG1 transgenic mouse founders, in which PLAG1 expression could be targeted to different tissues using the Cre/loxP system. MMTV-Cre-mediated targeted overexpression of PLAG1 in the salivary glands of double transgenic offspring mice, referred to as P1-MCre and P2-MCre mice, induced pleomorphic adenomas in this organ. Igf2, a genuine PLAG1 target gene, was highly upregulated in those tumours as well as in human pleomorphic adenomas of the salivary glands. These and previous observations in other PLAG1-induced tumours e.g. breast adenomyoepitheliomas emphasize the importance of Igf upregulation in such tumours. In this study, further evidence for the role of Igf2 in PLAG1-induced tumourigenesis, is reported. Inactivation of Igf2 in P1-MCre mice leads to a significant delay in tumour development. Since tumour development is not fully abrogated by inactivation of Igf2, other signalling pathways are likely to contribute to PLAG1-induced tumourigenesis as well. Further studies revealed that several genes such as H19, Dlk1, Gtl2, Igfbp2, Igfbp3 and genes involved in Wnt signalling, such as Wnt6, Cyclin D1 and ß-catenin are upregulated in P1-MCre mice in which Igf2 is inactivated. In conclusion, we clearly demonstrate upregulation of several genes associated with Igf and Wnt signalling in PLAG1-induced pleomorphic adenomas. Furthermore, inactivation of Igf2 does not affect upregulation of genes associated with Wnt signalling, which might suggest that both signalling pathways are involved.

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Section: Introductionmentioning

confidence: 93%

Upregulation of Igf and Wnt signalling associated genes in pleomorphic adenomas of the salivary glands in PLAG1 transgenic mice

Declercq

Dyck²,

Damme³

et al. 2008

Int J Oncol

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“…As the result of this gene fusion or t(3;8)(p21;q12), PLAG1 was activated, leading to its discovery and characterization (Kas et al, 1997). Lipoblastoma, a type of benign lipomatous tumor, often has shown chromosomal rearrangements involving the chromosomal region 8q11-13 and PLAG1 gene in this region (Hibbard et al, 2000;Gisselsson et al, 2001;Foa et al, 2002;Morerio et al, 2005;Brandal et al, 2006). The chromosomal rearrangements in lipoblastoma were associated with promoter swapping, in which the PLAG1 promoter element was found to be replaced by those from the hyaluronic acid synthase 2 (HAS2) or collagen (COL1A2) genes, due to 8q12-8q24.1 fusion and t(7;8), respectively, resulting in the transcriptional upregulation of PLAG1.…”

Section: Chromosomal Deletion and Rearrangementmentioning

confidence: 99%

LOT1 (ZAC1/PLAGL1) and its family members: Mechanisms and functions

Abdollahi

2006

Journal Cellular Physiology

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Lost-on-transformation 1 (LOT1) (PLAGL1/ZAC1) is a member of the novel subfamily of zinc-finger transcription factors, designated as PLAG family. The other members in this group include PLAG1 and PLAGL2, which share high homology with each other and with LOT1, particularly in their zinc-finger amino-terminal region. They are structurally similar but functionally different. For example, the LOT1 gene encodes a growth suppressor protein and is localized on human chromosome 6q24-25, a chromosomal region that is frequently deleted in many types of human cancers. The gene is maternally imprinted and is linked to developmental disorders such as growth retardation and transient neonatal diabetes mellitus (TNDM). LOT1 is a target of growth factor signaling pathway(s) and silenced by epigenetic mechanisms, as well as by the loss of heterozygosity in different tumor tissues. PLAG1 is a protooncogene that is localized on chromosome 8q12 and was found to be a target of several types of chromosomal rearrangement including the one identified in pleomorphic adenomas of the salivary gland. Since the discovery of the PLAG family members in 1997, much has been learned about their structure and function, as are summarized in this review. While the available data suggest that these proteins may play important roles in regulating normal physiological functions in the mammals, a great deal more about their signaling pathway(s), potential role in the complex pathologies such as cancer and developmental disorders, and functional relationship between different family members and splice variants still remains to be uncovered.

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“…Pleomorphic adenoma gene 1 (PLAG1) is a proto-oncogene on human chromosome 8q12 whose oncogenic activation is a crucial event in the formation of pleomorphic adenomas of the salivary glands (1, 2) and lipoblastomas (3)(4)(5). Recently, amplification and overexpression of PLAG1 was reported for hepatoblastoma, indicating that the PLAG1 gene might also be implicated in the molecular pathogenesis of this childhood neoplasia (6).…”

Section: Introductionmentioning

confidence: 99%

Salivary Gland Tumors in Transgenic Mice with Targeted PLAG1 Proto-Oncogene Overexpression

et al. 2005

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Pleomorphic adenoma gene 1 (PLAG1) proto-oncogene overexpression is implicated in various human neoplasias, including salivary gland pleomorphic adenomas. To further assess the oncogenic capacity of PLAG1, two independent PLAG1 transgenic mouse strains were established, PTMS1 and PTMS2, in which activation of PLAG1 overexpression is Cre mediated. Crossbreeding of PTMS1 or PTMS2 mice with MMTV-Cre transgenic mice was done to target PLAG1 overexpression to salivary and mammary glands, in the P1-Mcre/ P2-Mcre offspring. With a prevalence of 100% and 6%, respectively, P1-Mcre and P2-Mcre mice developed salivary gland tumors displaying various pleomorphic adenoma features. Moreover, histopathologic analysis of salivary glands of 1-week-old P1-Mcre mice pointed at early tumoral stages in epithelial structures. Malignant characteristics in the salivary gland tumors and frequent lung metastases were found in older tumor-bearing mice. PLAG1 overexpression was shown in all tumors, including early tumoral stages. The tumors revealed an up-regulation of the expression of two distinct, imprinted gene clusters (i.e., Igf2/H19 and Dlk1/Gtl2). With a latency period of about 1 year, 8% of the P2-Mcre mice developed mammary gland tumors displaying similar histopathologic features as the salivary gland tumors. In conclusion, our results establish the strong and apparently direct in vivo tumorigenic capacity of PLAG1 and indicate that the transgenic mice constitute a valuable model for pleomorphic salivary gland tumorigenesis and potentially for other glands as well. (Cancer Res 2005; 65(11): 4544-53)

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PLAG1-HAS2 fusion in lipoblastoma with masked 8q intrachromosomal rearrangement

Cited by 43 publications

References 4 publications

Upregulation of Igf and Wnt signalling associated genes in pleomorphic adenomas of the salivary glands in PLAG1 transgenic mice

Upregulation of Igf and Wnt signalling associated genes in pleomorphic adenomas of the salivary glands in PLAG1 transgenic mice

LOT1 (ZAC1/PLAGL1) and its family members: Mechanisms and functions

Salivary Gland Tumors in Transgenic Mice with Targeted PLAG1 Proto-Oncogene Overexpression

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