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U19/Eaf2 Knockout Causes Lung Adenocarcinoma, B-Cell Lymphoma

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U19/Eaf2 Knockout Causes Lung Adenocarcinoma, B-Cell Lymphoma Oncogene (2008) 27, 1536–1544 & 2008 Nature Publishing Group All rights reserved 0950-9232/08 $30.00 www.nature.com/onc ORIGINAL ARTICLE U19/Eaf2 knockout causes lung adenocarcinoma,B-cell lymphoma, hepatocellular carcinoma and prostatic intraepithelial neoplasia W Xiao1,2, Q Zhang1,8, G Habermacher1, X Yang3,4, A-y Zhang1,5, X Cai1, J Hahn1, J Liu5, M Pins3,4, L Doglio6, R Dhir7, J Gingrich5 and Z Wang1,4,5,6 1Department of Urology, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA; 2Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan, PR China; 3Department of Pathology, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA; 4Robert H Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA; 5Department of Urology, University of Pittsburgh Cancer Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; 6Center for Genetic Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA and 7Department of Pathology, University of Pittsburgh Cancer Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA Upregulated gene 19 (U19)/ELL-associated factor 2 Introduction (Eaf2) is a potential human tumor suppressor that exhibits frequent allelic loss and downregulation in high-grade Human upregulated gene 19 (U19)/ELL-associated prostate cancer. U19/Eaf2,along with its homolog Eaf1, factor 2 (Eaf2) is a potential prostate tumor suppressor has been reported to regulate transcriptional elongation (Xiao et al., 2003) that may also participate in acute via interaction with the eleven-nineteen lysine-rich leuke- myeloid leukemia development (Luo et al., 2001). mia (ELL) family of proteins. To further explore the However, a definitive role for U19/Eaf2 in tumor tumor-suppressive effects of U19/Eaf2,we constructed suppression remains unclear. Independent studies initi- and characterized a murine U19/Eaf2-knockout model. ally identified U19/Eaf2 as an androgen upregulated Homozygous or heterozygous deletion of U19/Eaf2 gene (U19) in the rat prostate (Wang et al., 1997) and resulted in high rates of lung adenocarcinoma,B-cell as a binding partner for eleven-nineteen lysine-rich lymphoma,hepatocellular carcinoma and prostate intrae- leukemia (ELL), making it the second member of pithelial neoplasia. Within the mouse prostate,U19/Eaf2 the Eaf family of proteins (Simone et al., 2001, 2003). deficiency enhanced cell proliferation and increased U19/Eaf2 shows significant sequence homology to the epithelial cell size. The knockout mice also exhibited original family member, Eaf1. ELL was discovered cardiac cell hypertrophy. These data indicate a role for as a fusion partner of MLL in the t(11; 19) (q23; U19/Eaf2 in growth suppression and cell size control as p13.1) chromosomal translocation associated with acute well as argue for U19/Eaf2 as a novel tumor suppressor in myeloid leukemia (Thirman et al., 1994). ELL binds to multiple mouse tissues. The U19/Eaf2 knockout mouse RNA polymerase II and acts as a transcription also provides a unique animal model for three important elongation factor whose targeted deletion leads to cancers: lung adenocarcinoma,B-cell lymphoma and embryonic lethality in mice (Shilatifard et al., 1996, hepatocellular carcinoma. 1997a, b; Mitani et al., 2000). Eaf2 also appears to be Oncogene (2008) 27, 1536–1544; doi:10.1038/sj.onc.1210786; important during embryogenesis, particularly for eye published online 17 September 2007 development (Li et al., 2003; Maurus et al., 2005). Both Eaf1 and U19/Eaf2 stimulate ELL elongation Keywords: U19/Eaf2; lung adenocarcinoma; B-cell lym- activity (Kong et al., 2005). In addition, ELL and phoma; hepatocellular carcinoma; prostate cancer; tumor Eaf1 colocalize to nuclear suborganelles called Cajal suppressor bodies (Polak et al., 2003) thought to be involved in nucleoli formation, RNA processing and transport of small ribonucleoproteins (Gall, 2003; Cioce and Lamond, 2005). Studies by Luo et al. (2001) argue that the Eaf proteins are important in MLL–ELL leukemo- genesis. Our previous studies showed that U19/Eaf2 inhibits xenograft prostate tumor growth and is Correspondence: Dr Z Wang, Department of Urology, University of downregulated in prostate cancer cell lines (Xiao et al., Pittsburgh, Shadyside Medical Center, Suite G40, 5200 Centre 2003). Moreover, a high frequency of loss of hetero- Avenue, Pittsburgh, PA 15232, USA. zygosity (LOH, 82.6%) and homozygous deletion (8%) E-mail: [email protected] was noted in high-grade human prostate cancers (Xiao 8Current address: UCLA Immunogenetics Center, Los Angeles, CA 90095, USA. et al., 2003). These findings link U19/Eaf2 with two Received 17 March 2007; revised 13 August 2007; accepted 13 August major human cancers—prostate cancer and acute myeloid 2007; published online 17 September 2007 leukemia. U19/Eaf2 as a novel tumor suppressor W Xiao et al 1537 To further test the hypothesis that U19/Eaf2 is a demonstrated the deletion of exon 2 in both isoforms mammalian tumor suppressor, we constructed and in the homologous knockout mice (data not shown), characterized a murine knockout model. The U19/Eaf2 while reverse transcriptase–polymerase chain reaction knockout mice develop B-cell lymphoma, lung adeno- showed the lack of the wild-type U19/Eaf2 transcript carcinoma, hepatocellular carcinoma (HCC) and prostatic (Figure 1f). Western blotting of mouse embryo fibro- intraepithelial neoplasia with high frequency. blasts (MEFs) isolated from wild-type and U19/Eaf2 knockout mice corroborated the absence of U19/Eaf2 expression in knockouts (Figure 1g). Using real-time RT–PCR, we found no significant difference in Eaf1, Results ELL1 and ELL2 expression between wild-type and U19/ Eaf2-KO specimens from the spleen, liver, kidney and Generation of U19/Eaf2 knockout mice MEF cells (data not shown). We first evaluated the expression pattern of U19/Eaf2 in Intercrosses of U19/Eaf2 heterozygous knockout mice mice. Using semiquantitative reverse transcription in either an isogenic 129P2/Ola Hsd background or in a (RT)–PCR, we detected U19/Eaf2 mRNA in all 12 129P2/Ola-C57BL/6J mixed genetic background yielded mouse tissues surveyed (Figure 1a). Next, we disrupted U19/Eaf2-null offspring at Mendelian ratios at birth the U19/Eaf2 gene by homologous recombination. The (data not shown). Within the first 4 months after birth, mouse U19/Eaf2 gene contains six exons encompassing homozygous mutants and their wild-type littermates approximately 34.5 kb of DNA on mouse chromosome were indistinguishable. Given the androgen-dependent 16 while the alternatively spliced isoform lacks exon 3. regulation of U19/Eaf2 in the prostate, analyses were To create the knockout, a targeting vector was designed performed only in male mice. to replace exon 2 with a neomycin gene cassette Using 60 wild-type and 60 U19/Eaf2-null mice for a (Figure 1b), resulting in a reading frameshift and survival analysis, we found no difference in the viability termination codons in all three reading frames for both between these groups up to 4 months of age. No gross isoforms and deletion of over 85% of the amino acids in abnormalities were observed in the growth of the U19/ U19/Eaf2. Homologous recombination was confirmed Eaf2-null mice up to 24 months (data not shown). in the embryonic stem (ES) cells by PCR and Southern However, after 4 months, U19/Eaf2-null mice began to blot analysis (data not shown), and subsequently in the die, with 31.8% (19 of 60) mortality reached by 16 U19/Eaf2 mutant mice (Figures 1c–e). Sequence analysis months. These mice did not display any overt abnorm- of the entire open reading frame (ORF) of U19/Eaf2 alities and autopsies did not reveal any macroscopic Figure 1 U19/Eaf2 expression patterns and generation of U19/Eaf2-null mice. (a) RT–PCR detection of U19/Eaf2 mRNA and ribosomal protein L19 mRNA (control) in mouse tissues. (b) The genomic structure of mouse U19/Eaf2 and the targeting strategy. Exon 2 was replaced with a Neo gene. The positions of probes 1 and 2 for the Southern blot are indicated. (c and d) Southern blot analysis of genomic DNA, extracted from mouse tail, using the 30-flanking probe, Probe 2 (c), and the 50-flanking probe, Probe 1 (d). (e) PCR analysis of mouse tail genomic DNA. PCR primers amplified 508 bp from the wild-type and 231 bp from the targeted allele. M, marker size; C, control without template DNA. (f) RT–PCR analysis of U19/Eaf2 mRNA using total RNA from testes of wild-type and knockout mice. The 50 U19/Eaf2 primer is within exon 2, and the 30 primer is in exon 5. L19 is the control. (g) Endogenous U19/ Eaf2 expression in wild-type and U19/Eaf2-null MEFs. Blots of wild-type and U19-null MEFs were probed with antibodies against U19/Eaf2 and glyceraldehyde-3-phosphate dehydrogenase (GAPDH). Experiments were independently done at least twice. (h) The survival curve of U19/Eaf2-null mice (n ¼ 60) and their wild-type littermates (n ¼ 60). Oncogene U19/Eaf2 as a novel tumor suppressor W Xiao et al 1538 tumors. Beyond 16 months, sudden death was rare. In contrast, all of the wild-type (Figure 1h) and hetero- zygous (data not shown) littermates survived through- out the study. Cardiac enlargement in U19/Eaf2-null mice Because of the U19/Eaf2-null mice mortality, we did a thorough histological exam of a cohort of null and wild-type animals. Tissues from 6- to 12-month-old U19/ Eaf2-null mice revealed no tumors or gross abnormalities in the kidney, lung and brain. However, enlarged hearts were readily apparent in some of the U19/Eaf2-null mice. Cardiac enlargement may be related to cardiac arrest, a possible cause of death especially since no other vital organs displayed abnormalities. Detailed analysis revealed that cardiac enlargement occurred in 39.1% (18 of 46) of U19/Eaf2-homozygous knockout mice (Figure 2a).
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