The recurrent SET-NUP214 fusion as a new HOXA activation mechanism in pediatric T-cell acute lymphoblastic leukemia.
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The recurrent SET-NUP214 fusion as a new HOXA activation mechanism in pediatric T-cell acute lymphoblastic leukemia. / Pieter, Van Vlierberghe; van Grotel, Martine; Tchinda, Joëlle; Lee, Charles; Beverloo, H Berna; Spek, van der; Peter, J; Stubbs, Andrew; Cools, Jan; Nagata, Kyosuke; Fornerod, Maarten; Horstmann, Martin; Horstmann, Martin; Wering, van; Elisabeth, R; Soulier, Jean; Pieters, Rob; Meijerink, Jules P P.
in: BLOOD, Jahrgang 111, Nr. 9, 9, 2008, S. 4668-4680.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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T1 - The recurrent SET-NUP214 fusion as a new HOXA activation mechanism in pediatric T-cell acute lymphoblastic leukemia.
AU - Pieter, Van Vlierberghe
AU - van Grotel, Martine
AU - Tchinda, Joëlle
AU - Lee, Charles
AU - Beverloo, H Berna
AU - Spek, van der
AU - Peter, J
AU - Stubbs, Andrew
AU - Cools, Jan
AU - Nagata, Kyosuke
AU - Fornerod, Maarten
AU - Horstmann, Martin
AU - Horstmann, Martin
AU - Wering, van
AU - Elisabeth, R
AU - Soulier, Jean
AU - Pieters, Rob
AU - Meijerink, Jules P P
PY - 2008
Y1 - 2008
N2 - 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.
AB - 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.
M3 - SCORING: Zeitschriftenaufsatz
VL - 111
SP - 4668
EP - 4680
JO - BLOOD
JF - BLOOD
SN - 0006-4971
IS - 9
M1 - 9
ER -
