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.
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NEOPLASIA
The recurrent SET-NUP214 fusion as a new HOXA activation mechanism in pediatric T-cell acute lymphoblastic leukemia
Pieter Van Vlierberghe1,
Martine van Grotel1,
Joëlle Tchinda2,
Charles Lee2,
H. Berna Beverloo3,
Peter J. van der Spek4,
Andrew Stubbs4,
Jan Cools5,
Kyosuke Nagata6,
Maarten Fornerod7,
Jessica Buijs-Gladdines1,
Martin Horstmann8,
Elisabeth R. van Wering9,
Jean Soulier10,
Rob Pieters1, and
Jules P. P. Meijerink1
1 Department of Pediatric Oncology/Hematology, Erasmus Medical Center (MC) Sophia Children's Hospital, Rotterdam, The Netherlands;
2 Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA;
3 Department of Clinical Genetics, Erasmus MC, Rotterdam, The Netherlands;
4 Department of Bioinformatics, Erasmus MC, Rotterdam, The Netherlands;
5 Department of Molecular and Developmental Genetics, Flanders Interuniversity Institute for Biotechnology (VIB), University of Leuven, Leuven, Belgium;
6 Department of Infection Biology, Graduate School of Comprehensive Human Sciences and Institute of Basic Medical Sciences, University of Tsukuba, Tsukuba, Japan;
7 Department of Tumor Biology, The Netherlands Cancer Institute, Amsterdam, The Netherlands;
8 German Co-operative Study Group for Childhood Acute Lymphoblastic Leukemia (COALL), Hamburg, Germany;
9 Dutch Childhood Oncology Group (DCOG), The Hague, The Netherlands; and
10 Hematology Laboratory, Hôpital Saint-Louis, Paris, France
T-cell acute lymphoblastic leukemia (T-ALL) is mostly characterized by specific chromosomal abnormalities, some occurring in a mutually exclusive manner that possibly delineate specific T-ALL subgroups. One subgroup, including MLL-rearranged, CALM-AF10 or inv (7)(p15q34) patients, 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 patients with elevated HOXA levels. Using microarray-based comparative genomic hybridization (array-CGH), a cryptic and recurrent deletion, del (9)(q34.11q34.13), was exclusively identified in 3 of these 5 patients. This deletion results in a conserved SET-NUP214 fusion product, which 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, which 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.
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