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Blood, 1 May 2008, Vol. 111, No. 9, pp. 4668-4680. Prepublished online as a Blood First Edition Paper on February 25, 2008; DOI 10.1182/blood-2007-09-111872. This Article Full Text (PDF) Supplemental Tables and Figures All Versions of this Article: blood-2007-09-111872v1 111/9/4668    most recent Alert me when this article is cited Alert me if a correction is posted 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 CrossRef Google Scholar Articles by Van Vlierberghe, P. Articles by Meijerink, J. P.P. PubMed PubMed Citation Articles by Van Vlierberghe, P. Articles by Meijerink, J. P.P. Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted September 10, 2007 Accepted February 12, 2008 The recurrent SET-NUP214 fusion as a new HOXA activation mechanism in pediatric T-cell acute lymphoblastic leukemia Pieter Van Vlierberghe, Martine van Grotel, Joelle Tchinda, Charles Lee, H. Berna Beverloo, Peter J van der Spek, Andrew Stubbs, Jan Cools, Kyosuke Nagata, Maarten Fornerod, Jessica Buijs-Gladdines, Martin Horstmann, Elisabeth R van Wering, Jean Soulier, Rob Pieters, and Jules P.P. Meijerink* Department of Pediatric Oncology/Hematology, Erasmus MC / Sophia Children's Hospital, Rotterdam, Netherlands Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, United States Department of Clinical Genetics, Erasmus MC, Rotterdam, Netherlands Department of Bioinformatics, Erasmus MC, Rotterdam, Netherlands Department of Molecular and Developmental genetics, Flanders Interuniversity Institute for Biotechnology (VIB), University of Leuven, Leuven, Belgium Department of Infection Biology, Graduate School of Comprehensive Human Sciences, and Institute of Basic Medical Sciences, University of Tsukuba, Tsukuba, Japan Department of Tumor biology, The Netherlands Cancer Institute, Amsterdam, Netherlands German Co-operative study group for childhood acute lymphoblastic leukemia (COALL), Hamburg, Germany Dutch Childhood Oncology Group (DCOG), The Hague, Netherlands Hematology Laboratory, APHP, Hopital Saint-Louis, Paris, France * Corresponding author; email: j.meijerink{at}erasmusmc.nl. T-cell acute lymphoblastic leukemia (T-ALL) is mostly characterized by specific chromosomal abnormalities, some occurring in a mutually exclusive manner possibly delineating specific T-ALL subgroups. One subgroup, including MLL-rearranged, CALM-AF10 or inv(7)(p15q34) cases, is characterized by elevated expression of HOXA genes. Using a gene expression based clustering analysis of 67 T-ALL cases with recurrent molecular genetic abnormalities and 25 samples lacking apparent aberrations, we identified 5 new cases with elevated HOXA levels. Using array-CGH, a cryptic and recurrent deletion, del(9)(q34.11q34.13), was exclusively identified in 3 of these 5 cases. This deletion results in a conserved SET-NUP214 fusion product, that was also identified in the T-ALL cell line LOUCY. SET-NUP214 binds in the promoter regions of specific HOXA genes, where it interacts with CRM1 and DOT1L that may transcriptionally activate specific members of the HOXA cluster. Targeted inhibition of SET-NUP214 by siRNA abolished expression of HOXA genes, inhibited proliferation and induced differentiation in LOUCY but not in other T-ALL lines. We conclude that SET-NUP214 may contribute to the pathogenesis of T-ALL by enforcing T-cell differentiation arrest. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

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