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Blood, 15 May 2005, Vol. 105, No. 10, pp. 4060-4069. Prepublished online as a Blood First Edition Paper on January 27, 2005; DOI 10.1182/blood-2004-09-3704. This Article Full Text Full Text (PDF) All Versions of this Article: 2004-09-3704v1 105/10/4060    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Keats, J. J. Articles by Pilarski, L. M. Search for Related Content PubMed PubMed Citation Articles by Keats, J. J. Articles by Pilarski, L. M. Related Collections Immunobiology Neoplasia Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  NEOPLASIA Overexpression of transcripts originating from the MMSET locus characterizes all t(4;14)(p16;q32)-positive multiple myeloma patients Jonathan J. Keats, Christopher A. Maxwell, Brian J. Taylor, Michael J. Hendzel, Marta Chesi, P. Leif Bergsagel, Loree M. Larratt, Michael J. Mant, Tony Reiman, Andrew R. Belch, and Linda M. Pilarski From the Department of Oncology, University of Alberta & Cross Cancer Institute, Edmonton, AB Canada; the Department of Medicine, University of Alberta, Edmonton, AB Canada; and the Department of Hematology/Oncology, Mayo Clinic, Scottsdale, AZ. Multiple myeloma (MM) is a B-lineage malignancy characterized by diverse genetic subtypes and clinical outcomes. The recurrent immunoglobulin heavy chain (IgH) switch translocation, t(4;14)(p16;q32), is associated with poor outcome, though the mechanism is unclear. Quantitative reverse-transcription–polymerase chain reaction (RT-PCR) for proposed target genes on a panel of myeloma cell lines and purified plasma cells showed that only transcripts originating from the WHSC1/MMSET/NSD2 gene are uniformly dysregulated in all t(4;14)POS patients. The different transcripts detected, multiple myeloma SET domain containing protein (MMSET I), MMSET II, Exon 4a/MMSET III, and response element II binding protein (RE-IIBP), are produced by alternative splicing and alternative transcription initiation events. Translation of the various transcripts, including those from major breakpoint region 4-2 (MB4-2) and MB4-3 breakpoint variants, was confirmed by transient transfection and immunoblotting. Green fluorescent protein (GFP)–tagged MMSET I and II, corresponding to proteins expressed in MB4-1 patients, localized to the nucleus but not nucleoli, whereas the MB4-2 and MB4-3 proteins concentrate in nucleoli. Cloning and localization of the Exon 4a/MMSET III splice variant, which contains the protein segment lost in the MB4-2 variant, identified a novel protein domain that prevents nucleolar localization. Kinetic studies using photobleaching suggest that the breakpoint variants are functionally distinct from wild-type proteins. In contrast, RE-IIBP is universally dysregulated and also potentially functional in all t(4;14)POS patients irrespective of fibroblast growth factor receptor 3 (FGFR3) expression or breakpoint type. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: J.-Y. Kim, H. J. Kee, N.-W. Choe, S.-M. Kim, G.-H. Eom, H. J. Baek, H. Kook, H. Kook, and S.-B. Seo Multiple Myeloma-Related WHSC1/MMSET Isoform RE-IIBP Is a Histone Methyltransferase with Transcriptional Repression Activity Mol. Cell. Biol., March 15, 2008; 28(6): 2023 - 2034. [Abstract] [Full Text] [PDF] J. Marango, M. Shimoyama, H. Nishio, J. A. Meyer, D.-J. Min, A. Sirulnik, Y. Martinez-Martinez, M. Chesi, P. L. Bergsagel, M.-M. Zhou, et al. The MMSET protein is a histone methyltransferase with characteristics of a transcriptional corepressor Blood, March 15, 2008; 111(6): 3145 - 3154. [Abstract] [Full Text] [PDF] J. Li, C. Yin, H. Okamoto, H. Mushlin, B. M. Balgley, C. S. Lee, K. Yuan, B. Ikejiri, S. Glasker, A. O. Vortmeyer, et al. Identification of a novel proliferation-related protein, WHSC1 4a, in human gliomas Neuro-oncol, February 1, 2008; 10(1): 45 - 51. [Abstract] [Full Text] [PDF] Z. Bar-Joseph, Z. Siegfried, M. Brandeis, B. Brors, Y. Lu, R. Eils, B. D. Dynlacht, and I. Simon Genome-wide transcriptional analysis of the human cell cycle identifies genes differentially regulated in normal and cancer cells PNAS, January 22, 2008; 105(3): 955 - 960. [Abstract] [Full Text] [PDF] J. Lauring, A. M. Abukhdeir, H. Konishi, J. P. Garay, J. P. Gustin, Q. Wang, R. J. Arceci, W. Matsui, and B. H. Park The multiple myeloma associated MMSET gene contributes to cellular adhesion, clonogenic growth, and tumorigenicity Blood, January 15, 2008; 111(2): 856 - 864. [Abstract] [Full Text] [PDF] J. VanDijken, G. V. Kaigala, J. Lauzon, A. Atrazhev, S. Adamia, B. J. Taylor, T. Reiman, A. R. Belch, C. J. Backhouse, and L. M. Pilarski Microfluidic Chips for Detecting the t(4;14) Translocation and Monitoring Disease during Treatment Using Reverse Transcriptase-Polymerase Chain Reaction Analysis of IgH-MMSET Hybrid Transcripts J. Mol. Diagn., July 1, 2007; 9(3): 358 - 367. [Abstract] [Full Text] [PDF] I. M. Krouwels, K. Wiesmeijer, T. E. Abraham, C. Molenaar, N. P. Verwoerd, H. J. Tanke, and R. W. Dirks A glue for heterochromatin maintenance: stable SUV39H1 binding to heterochromatin is reinforced by the SET domain J. Cell Biol., August 15, 2005; 170(4): 537 - 549. [Abstract] [Full Text] [PDF]

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