title: The recurrent SET-NUP214 fusion as a new HOXA activation mechanism in pediatric T-cell acute lymphoblastic leukemia.
abstract: 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.
authors.affiliation: Department of Pediatric Oncology/Hematology, Erasmus Medical Center Sophia Children's Hospital, Rotterdam, The Netherlands.
authors.forename: Pieter
authors.initials: P
authors.lastname: Van Vlierberghe
authors.forename: Martine
authors.initials: M
authors.lastname: van Grotel
authors.forename: Joëlle
authors.initials: J
authors.lastname: Tchinda
authors.forename: Charles
authors.initials: C
authors.lastname: Lee
authors.forename: H Berna
authors.initials: HB
authors.lastname: Beverloo
authors.forename: Peter J
authors.initials: PJ
authors.lastname: van der Spek
authors.forename: Andrew
authors.initials: A
authors.lastname: Stubbs
authors.forename: Jan
authors.initials: J
authors.lastname: Cools
authors.forename: Kyosuke
authors.initials: K
authors.lastname: Nagata
authors.forename: Maarten
authors.initials: M
authors.lastname: Fornerod
authors.forename: Jessica
authors.initials: J
authors.lastname: Buijs-Gladdines
authors.forename: Martin
authors.initials: M
authors.lastname: Horstmann
authors.forename: Elisabeth R
authors.initials: ER
authors.lastname: van Wering
authors.forename: Jean
authors.initials: J
authors.lastname: Soulier
authors.forename: Rob
authors.initials: R
authors.lastname: Pieters
authors.forename: Jules P P
authors.initials: JP
authors.lastname: Meijerink
mesh_terms: D002454:Cell Differentiation; D002648:Child; D002868:Chromosomal Proteins, Non-Histone / Q000235:genetics*; D016000:Cluster Analysis; D004268:DNA-Binding Proteins; D020869:Gene Expression Profiling; D056488:Histone Chaperones; D018398:Homeodomain Proteins / Q000235:genetics*; D006801:Humans; D015459:Leukemia-Lymphoma, Adult T-Cell / Q000209:etiology / Q000235:genetics*; D028861:Nuclear Pore Complex Proteins / Q000235:genetics*; D015514:Oncogene Proteins, Fusion / Q000502:physiology*; D011485:Protein Binding; D012008:Recurrence; D017384:Sequence Deletion; D014157:Transcription Factors / Q000235:genetics*
chemical_list: D002868:Chromosomal Proteins, Non-Histone; D004268:DNA-Binding Proteins; D056488:Histone Chaperones; D018398:Homeodomain Proteins; C085914:NUP214 protein, human; D028861:Nuclear Pore Complex Proteins; D015514:Oncogene Proteins, Fusion; C513473:SET protein, human; D014157:Transcription Factors; C088144:HoxA protein