PLAG1 alterations in lipoblastoma: involvement in varied mesenchymal cell types and evidence for alternative oncogenic mechanisms.

Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts 02115, USA.
American Journal Of Pathology (Impact Factor: 4.6). 10/2001; 159(3):955-62.
Source: PubMed

ABSTRACT Lipoblastomas are rare soft tissue tumors that occur primarily in young children. They typically contain variably differentiated adipocytes, primitive mesenchymal cells, myxoid matrix, and fibrous trabeculae. Abnormalities in chromosome 8, leading to rearrangements of the PLAG1 gene, were demonstrated recently in four lipoblastomas. In the present report, we determine the frequency of PLAG1 alterations in 16 lipoblastomas from children aged 13 years or younger, and we also evaluate the stages of lipoblastoma differentiation at which PLAG1 genomic alterations are found. Eleven lipoblastomas (69%), including those with either classic or lipoma-like histology, had rearrangements of the 8q12 PLAG1 region. Another three lipoblastomas had polysomy for chromosome 8 in the absence of PLAG1 rearrangement. Only two cases (13%) lacked a chromosome 8 abnormality. Notably, the lipoblastomas with chromosome 8 polysomy had up to five copies of chromosome 8 as an isolated cytogenetic finding in an otherwise diploid cell. We also demonstrate that PLAG1 alterations are found in a spectrum of mesenchymal cell types in lipoblastomas, including lipoblasts, mature adipocytes, primitive mesenchymal cells, and fibroblast-like cells. This finding is consistent with neoplastic origin in a primitive mesenchymal precursor and with variable differentiation to a mature adipocyte end-point. Hence, our studies provide biological validation for the clinical observation that lipoblastomas can evolve into mature, lipoma-like, lesions. They also suggest that PLAG1 dosage alterations caused by polysomy 8 might represent an alternative oncogenic mechanism in lipoblastoma.

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Available from: Raf Sciot, Jul 29, 2015
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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. "
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    ABSTRACT: 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.
    Journal of Cellular Physiology 01/2007; 210(1):16-25. DOI:10.1002/jcp.20835 · 3.87 Impact Factor
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    • "Promoter-swapping events with hyaluronic acid synthase 2 (HSA2) or collagen (COL1A2) genes as well as with so-far-uncharacterized fusion partners also are presumed to be responsible for up-regulation of PLAG1 in approximately 70% of lipoblastomas (Hibbard et al., 2000). Interestingly, polysomy for chromosome 8, with up to five copies of chromosome 8 in otherwise diploid cells, was found in the absence of PLAG1 rearrangements in 3 of 16 lipoblastomas , suggesting that PLAG1 dosage alterations caused by polysomy 8 might represent an alternative oncogenic mechanism in lipoblastoma (Gisselsson et al., 2001). Overexpression of PLAG1 has also been found in other mesenchymal tumors, that is, in two uterine leiomyomas and in one leiomyosarcoma (Astrom et al., 1999). "
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    ABSTRACT: There is evidence that 8q amplification is associated with poor prognosis in hepatoblastoma. A previous comparative genomic hybridization analysis identified a critical region in chromosomal bands 8q11.2-q13. Using restriction landmark genomic scanning in combination with a virtual genome scan, we showed that this region is delineated by sequences within contig NT_008183 of chromosomal subbands 8q11.22-q11.23. A real-time PCR-based genomic copy number assay of 20 hepatoblastomas revealed gain or amplification in this critical chromosomal region in eight tumors. The expression of four genes and expressed sequence tags (ESTs) within this newly defined region was assayed by real-time reverse transcriptase polymerase chain reaction (RT-PCR) in four tumors with and six tumors without gain or amplification. The PLAG1 oncogene was found to be highly expressed in all but one tumor compared to normal liver tissue. Furthermore, quantitative RT-PCR revealed that the expression level of the developmentally regulated transcription factor PLAG1 was 3-12 times greater in hepatoblastoma tumors and cell lines compared to age-matched normal liver and comparable to the expression in fetal liver tissue. PLAG1 has been shown be a transcriptional activator of IGF2 in other tumor types. Using luciferase reporter assays, we demonstrated that PLAG1 transactivates transcription from the embryonic IGF2 promoter P3, also in hepatoblastoma cell lines. Thus, our results provide evidence that PLAG1 overexpression may be responsible for the frequently observed up-regulation of IGF2 in hepatoblastoma and therefore may be implicated in the molecular pathogenesis of this childhood neoplasia.
    Genes Chromosomes and Cancer 02/2004; 39(2):126-37. DOI:10.1002/gcc.10307 · 3.84 Impact Factor
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    • "are oncogenes involved in various malignancies (Aman et al., 1999; Astrom et al., 1999; Astrom et al., 2000; Castilla et al., 2004; Declercq et al., 2005; Gisselsson et al., 2001; Hensen et al., 2002; Hibbard et al., 2000; Kas et al., 1997; Landrette et al., 2004; Voz et al., 1998; Zatkova et al., 2004). Thus studying their regulatory mechanisms is of particular interest, because it may lead to novel approaches to modulate the activities of PLAG1/PLAGL2 in associated malignancies. "
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    ABSTRACT: [School of Medicine] Department of Pharmacology. Thesis (Ph. D.)--Case Western Reserve University, 2006. Includes bibliographical references. Requires Adobe Acrobat Reader for viewing.
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