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Blood, 15 August 2004, Vol. 104, No. 4, pp. 1127-1136. Prepublished online as a Blood First Edition Paper on April 20, 2004; DOI 10.1182/blood-2003-10-3550. This Article Full Text (PDF) All Versions of this Article: 2003-10-3550v1 104/4/1127    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 HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Gurevich, R. M Articles by Humphries, R. K Search for Related Content PubMed PubMed Citation Articles by Gurevich, R. M Articles by Humphries, R. K Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted October 16, 2003 Accepted April 3, 2004 The NUP98-Topoisomerase I AML-associated fusion gene has potent leukemogenic activities independent of an engineered catalytic site mutation Rhonna M Gurevich, Peter D Aplan, and Richard K Humphries* Terry Fox Laboratory, BC Cancer Agency, Vancouver, BC, Canada National Naval Medical Center, National Cancer Institute, Bethesda, MD, USA Terry Fox Laboratory, BC Cancer Agency, Vancouver, BC, Canada; Medicine, University of British Columbia, Vancouver, BC, Canada * Corresponding author; email: khumphri{at}bccrc.ca. Chromosomal rearrangements of the 11p15 locus have been identified in hematopoietic malignancies, resulting in translocations involving the N-terminal portion of the nucleoporin gene NUP98. Fifteen different fusion partner genes have been identified for NUP98 and over half of these are homeobox transcription factors. By contrast, the NUP98 fusion partner in t(11;20) is Topoisomerase I (TOP1), a catalytic enzyme recognized for its key role in relaxing supercoiled DNA. We now show that retrovirally engineered expression of NUP98-TOP1 in murine bone marrow confers a potent in vitro growth advantage and a block in differentiation in hematopoietic precursors, evidenced by a competitive growth advantage in liquid culture, increased replating efficient of CFC and a marked increase in spleen colony forming cell output. Moreover, in a murine bone marrow transplantation model, NUP98-TOP1 expression led to a lethal, transplantable leukemia characterized by extremely high white cell counts, splenomegaly and mild anemia. Strikingly, a mutation to a TOP1 site to inactivate the isomerase activity, essentially left unaltered the growth promoting and leukemogenic effects of NUP98-TOP1. These findings, together with similar biological effects reported for NUP98-HOX fusions, suggest unexpected, overlapping functions of NUP98 fusion genes, perhaps related to common DNA binding properties. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: M. Heuser, L. M. Sly, B. Argiropoulos, F. Kuchenbauer, C. Lai, A. Weng, M. Leung, G. Lin, C. Brookes, S. Fung, et al. Modeling the functional heterogeneity of leukemia stem cells: role of STAT5 in leukemia stem cell self-renewal Blood, November 5, 2009; 114(19): 3983 - 3993. [Abstract] [Full Text] [PDF] M. Heuser, D. B. Yap, M. Leung, T. R. de Algara, A. Tafech, S. McKinney, J. Dixon, R. Thresher, B. Colledge, M. Carlton, et al. Loss of Mll5 results in pleiotropic hematopoietic defects, reduced neutrophil immune function, and extreme sensitivity to DNA demethylation Blood, February 12, 2009; 113(7): 1432 - 1443. [Abstract] [Full Text] [PDF] D. Jankovic, P. Gorello, T. Liu, S. Ehret, R. La Starza, C. Desjobert, F. Baty, M. Brutsche, P.-S. Jayaraman, A. Santoro, et al. Leukemogenic mechanisms and targets of a NUP98/HHEX fusion in acute myeloid leukemia Blood, June 15, 2008; 111(12): 5672 - 5682. [Abstract] [Full Text] [PDF] M. Heuser, B. Argiropoulos, F. Kuchenbauer, E. Yung, J. Piper, S. Fung, R. F. Schlenk, K. Dohner, T. Hinrichsen, C. Rudolph, et al. MN1 overexpression induces acute myeloid leukemia in mice and predicts ATRA resistance in patients with AML Blood, September 1, 2007; 110(5): 1639 - 1647. [Abstract] [Full Text] [PDF] X.-T. Bai, B.-W. Gu, T. Yin, C. Niu, X.-D. Xi, J. Zhang, Z. Chen, and S.-J. Chen Trans-Repressive Effect of NUP98-PMX1 on PMX1-Regulated c-FOS Gene through Recruitment of Histone Deacetylase 1 by FG Repeats. Cancer Res., May 1, 2006; 66(9): 4584 - 4590. [Abstract] [Full Text] [PDF] P. Klener, M. Szynal, Y. Cleuter, M. Merimi, H. Duvillier, F. Lallemand, C. Bagnis, P. Griebel, C. Sotiriou, A. Burny, et al. Insights into Gene Expression Changes Impacting B-Cell Transformation: Cross-Species Microarray Analysis of Bovine Leukemia Virus Tax-Responsive Genes in Ovine B Cells J. Virol., February 15, 2006; 80(4): 1922 - 1938. [Abstract] [Full Text] [PDF] K. Nebral, H. H. Schmidt, O. A. Haas, and S. Strehl NUP98 Is Fused to Topoisomerase (DNA) II{beta} 180 kDa (TOP2B) in a Patient with Acute Myeloid Leukemia with a New t(3;11)(p24;p15) Clin. Cancer Res., September 15, 2005; 11(18): 6489 - 6494. [Abstract] [Full Text] [PDF]

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