Epigenetic regulator MLL2 shows altered expression in cancer cell lines and tumors from human breast and colon

Natarajan, Thanemozhi G.; Kallakury, Bhaskar; Sheehan, Christine E.; Bartlett, Margaret B.; Ganesan, Natarajan; Preet, Anju; Ross, Jeffrey S.; Fitzgerald, Kevin T.

doi:10.1186/1475-2867-10-13

Cited by 47 publications

(39 citation statements)

References 29 publications

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“…MLL4, a histone-lysine N-methyltransferase, is a part of the ASC-2 complex implicated in the p53 tumor suppressor pathway (Lee et al 2009). Other members of the MLL family are frequently mutated in solid tumors (Lee et al 2008;Natarajan et al 2010). This viral integration within the MLL4 gene is accompanied by a >20-fold increase in the MLL4 transcript level ( Fig.…”

Section: Transcriptional and Genomic Impact Of Hbv Integrationmentioning

confidence: 99%

The effects of hepatitis B virus integration into the genomes of hepatocellular carcinoma patients

Jiang¹,

Jhunjhunwala²,

Liu³

et al. 2012

Genome Res.

270

281

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Hepatitis B virus (HBV) infection is a leading risk factor for hepatocellular carcinoma (HCC). HBV integration into the host genome has been reported, but its scale, impact and contribution to HCC development is not clear. Here, we sequenced the tumor and nontumor genomes (>803 coverage) and transcriptomes of four HCC patients and identified 255 HBV integration sites. Increased sequencing to 2403 coverage revealed a proportionally higher number of integration sites. Clonal expansion of HBV-integrated hepatocytes was found specifically in tumor samples. We observe a diverse collection of genomic perturbations near viral integration sites, including direct gene disruption, viral promoterdriven human transcription, viral-human transcript fusion, and DNA copy number alteration. Thus, we report the most comprehensive characterization of HBV integration in hepatocellular carcinoma patients. Such widespread random viral integration will likely increase carcinogenic opportunities in HBV-infected individuals.[Supplemental material is available for this article.] . HBV integration into the host genome has been reported both in tumors (Gozuacik et al. 2001;Murakami et al. 2005;Saigo et al. 2008) and in nontumor liver tissue from HBV-infected individuals (Mason et al. 2010), although such integration is not essential for HBV replication. The relative extent, mutation model, and the functional impact of HBV integration in host genomes is not clear due to the lack of an unbiased approach to identify and quantify genome-wide HBV integration sites. Recent advances in sequencing technologies (Meyerson et al. 2010) provide an opportunity to investigate the global extent, mutation model, and functional impact of viral integration in the host genome. Recently, a primary hepatitis C virus-infected HCC patient has been subjected to whole-genome sequencing, and many somatic mutations were reported (Totoki et al. 2011). However, as an RNA virus, HCV never integrates into the host genome during its life cycle; therefore, liver cancer with HCV infection is not an optimal model to study viral-human genomic interactions. To that end, sequencing the genome and transcriptome of an HBV-positive HCC patient provides a great opportunity to reveal the functional impact of viral integration on the host genome.

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Section: Transcriptional and Genomic Impact Of Hbv Integrationmentioning

confidence: 99%

The effects of hepatitis B virus integration into the genomes of hepatocellular carcinoma patients

Jiang¹,

Jhunjhunwala²,

Liu³

et al. 2012

Genome Res.

270

281

View full text Add to dashboard Cite

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“…3). In addition, MLL4 has been found to be overexpressed in breast and colorectal cell lines (4). MLL1 and MLL4 play essential roles in regulating the expression of genes that are involved in cell differentiation and early embryonic development, among which the most notable and best-established are the Homeobox (Hox) genes (5,6).…”

mentioning

confidence: 99%

Global identification of MLL2-targeted loci reveals MLL2’s role in diverse signaling pathways

Guo

Chang

Wortham

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

106

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Myeloid/lymphoid or mixed-lineage leukemia (MLL)-family genes encode histone lysine methyltransferases that play important roles in epigenetic regulation of gene transcription. MLL genes are frequently mutated in human cancers. Unlike MLL1, MLL2 (also known as ALR/MLL4) and its homolog MLL3 are not well-understood. Specifically, little is known regarding the extent of global MLL2 involvement in the regulation of gene expression and the mechanism underlying its alterations in driving tumorigenesis. Here we profile the global loci targeted by MLL2. A combinatorial analysis of the MLL2 binding profile and gene expression in MLL2 wild-type versus MLL2-null isogenic cell lines identified direct transcriptional target genes and revealed the connection of MLL2 to multiple cellular signaling pathways, including the p53 pathway, cAMP-mediated signaling, and cholestasis signaling. In particular, we demonstrate that MLL2 participates in retinoic acid receptor signaling by promoting retinoic acid-responsive gene transcription. Our results present a genome-wide integrative analysis of the MLL2 target loci and suggest potential mechanisms underlying tumorigenesis driven by MLL2 alterations.tumor suppressor | somatic targeting | S100A gene cluster

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“…By contrast, tumor-related functions of MLL2 and MLL4 are largely unknown. Rather, MLL2 expression is overexpressed in colon and breast cancers [32], and MLL4 gene is amplified in glioblastoma and pancreatic cancers [21]. These data suggest a possibility that hyperfunction of MLL2 and MLL4 is involved in cancer pathogenesis.…”

Section: Discussionmentioning

confidence: 90%

Mutational and expressional analysis of MLL genes in gastric and colorectal cancers with microsatellite instability

Je¹,

Yoo²,

LEE³

2012

neo

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MLL genes encode histone methyltransferases that are required for proper expression of a variety of genes. The pathologic implications of MLL genes have been studied not only in leukemias, but also in some solid cancers. We found in a public database that MLL, MLL2, MLL3, MLL4 and MLL5 genes had mononucleotide repeats that might be mutated in cancers with microsatellite instability (MSI). Frameshift mutations in a repeat of MLL3 have been found in colorectal cancers (CRC), but there is no frameshift mutation data of the other genes. In this study, we analyzed these repeats in 32 gastric cancers (GC) with high MSI (MSI-H), 59 GC with low MSI (MSI-L)/stable MSI (MSS), 40 CRC with MSI-H and 59 CRC with MSI-L/MSS by single-strand conformation polymorphism and DNA sequencing. We also analyzed MLL3 expression in GC and CRC tissues using immunohistochemistry. We found MLL, MLL2, MLL3 and MLL5 frameshift mutations in two (one GC and one CRC), three (one GC and two CRC), 17 (14 GC and three CRC) and six (four GC and two CRC) cancers, respectively. They were detected exclusively in MSI-H cancers, but not in MSI-L/MSS cancers. All of the cancers with MLL3 mutations showed loss of MLL3 expression, and their values were significantly lower than in those without MLL3 mutation (50.9%). Of note, the GC with MSI-H had significantly higher incidences in both MLL mutations and MLL3 expression loss than the CRC with MSI-H. Our data indicate that frameshift mutations of MLL genes and loss of expression of MLL3 protein are common in GC and CRC with MSI-H.

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Epigenetic regulator MLL2 shows altered expression in cancer cell lines and tumors from human breast and colon

Cited by 47 publications

References 29 publications

The effects of hepatitis B virus integration into the genomes of hepatocellular carcinoma patients

The effects of hepatitis B virus integration into the genomes of hepatocellular carcinoma patients

Global identification of MLL2-targeted loci reveals MLL2’s role in diverse signaling pathways

Mutational and expressional analysis of MLL genes in gastric and colorectal cancers with microsatellite instability

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