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Blood, 15 June 2008, Vol. 111, No. 12, pp. 5672-5682. Prepublished online as a Blood First Edition Paper on April 10, 2008; DOI 10.1182/blood-2007-09-108175. This Article Full Text Full Text (PDF) Supplemental Tables and Figures All Versions of this Article: blood-2007-09-108175v1 blood-2007-09-108175v2 111/12/5672    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 CrossRef Citing Articles via Google Scholar Google Scholar Articles by Jankovic, D. Articles by Schwaller, J. Search for Related Content PubMed PubMed Citation Articles by Jankovic, D. Articles by Schwaller, J. Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  NEOPLASIA Leukemogenic mechanisms and targets of a NUP98/HHEX fusion in acute myeloid leukemia Dragana Jankovic1,*, Paolo Gorello2,*, Ting Liu1, Sabire Ehret1, Roberta La Starza2, Cecile Desjobert3, Florent Baty4, Martin Brutsche4, Padma-Sheila Jayaraman3,5, Alessandra Santoro6, Christina Mecucci2,, and Juerg Schwaller1, 1 Department of Research, University Hospital Basel, Basel, Switzerland; 2 Hematology and Bone Marrow Transplantation Unit, University of Perugia, Perugia, Italy; 3 Department of Biochemistry, University of Bristol, Bristol, United Kingdom; 4 Department for Internal Medicine, University Hospital Basel, Basel, Switzerland; 5 Division of Immunity and Infection, University of Birmingham, Birmingham, United Kingdom; and 6 Ospedale V. Cervello, Divisione di Ematologia, Palermo, Italy We have studied a patient with acute myeloid leukemia (AML) and t(10;11)(q23;p15) as the sole cytogenetic abnormality. Molecular analysis revealed a translocation involving nucleoporin 98 (NUP98) fused to the DNA-binding domain of the hematopoietically expressed homeobox gene (HHEX). Expression of NUP98/HHEX in murine bone marrow cells leads to aberrant self-renewal and a block in normal differentiation that depends on the integrity of the NUP98 GFLG repeats and the HHEX homeodomain. Transplantation of bone marrow cells expressing NUP98/HHEX leads to transplantable acute leukemia characterized by extensive infiltration of leukemic blasts expressing myeloid markers (Gr1+) as well as markers of the B-cell lineage (B220+). A latency period of 9 months and its clonal character suggest that NUP98/HHEX is necessary but not sufficient for disease induction. Expression of EGFP-NUP98/HHEX fusions showed a highly similar nuclear localization pattern as for other NUP98/homeodomain fusions, such as NUP98/HOXA9. Comparative gene expression profiling in primary bone marrow cells provided evidence for the presence of common targets in cells expressing NUP98/HOXA9 or NUP98/HHEX. Some of these genes (Hoxa5, Hoxa9, Flt3) are deregulated in NUP98/HHEX-induced murine leukemia as well as in human blasts carrying this fusion and might represent bona fide therapeutic targets. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

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