title: Cooperative genetic defects in TLX3 rearranged pediatric T-ALL.
abstract: T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive neoplastic disorder, in which multiple genetic abnormalities cooperate in the malignant transformation of thymocytes. About 20% of pediatric T-ALL cases are characterized by TLX3 expression due to a cryptic translocation t(5;14)(q35;q32). Although a number of collaborating genetic events have been identified in TLX3 rearranged T-ALL patients (NOTCH1 mutations, p15/p16 deletions, NUP214-ABL1 amplifications), further elucidation of additional genetic lesions could provide a better understanding of the pathogenesis of this specific T-ALL subtype. In this study, we used array-CGH to screen TLX3 rearranged T-ALL patients for new chromosomal imbalances. Array-CGH analysis revealed five recurrent genomic deletions in TLX3 rearranged T-ALL, including del(1)(p36.31), del(5)(q35), del(13)(q14.3), del(16)(q22.1) and del(19)(p13.2). From these, the cryptic deletion, del(5)(q35), was exclusively identified in about 25% of TLX3 rearranged T-ALL cases. In addition, 19 other genetic lesions were detected once in TLX3 rearranged T-ALL cases, including a cryptic WT1 deletion and a deletion covering the FBXW7 gene, an U3-ubiquitin ligase that mediates the degradation of NOTCH1, MYC, JUN and CyclinE. This study provides a genome-wide overview of copy number changes in TLX3 rearranged T-ALL and offers great new challenges for the identification of new target genes that may play a role in the pathogenesis of T-ALL.
authors.affiliation: Department of Pediatric Oncology/Hematology, Erasmus MC/Sophia Children's Hospital, Rotterdam, The Netherlands.
authors.forename: P
authors.initials: P
authors.lastname: Van Vlierberghe
authors.forename: I
authors.initials: I
authors.lastname: Homminga
authors.forename: L
authors.initials: L
authors.lastname: Zuurbier
authors.forename: J
authors.initials: J
authors.lastname: Gladdines-Buijs
authors.forename: E R
authors.initials: ER
authors.lastname: van Wering
authors.forename: M
authors.initials: M
authors.lastname: Horstmann
authors.forename: H B
authors.initials: HB
authors.lastname: Beverloo
authors.forename: R
authors.initials: R
authors.lastname: Pieters
authors.forename: J P P
authors.initials: JP
authors.lastname: Meijerink
mesh_terms: D018797:Cell Cycle Proteins / Q000235:genetics; D002648:Child; D002869:Chromosome Aberrations; D004252:DNA Mutational Analysis; D044783:F-Box Proteins / Q000235:genetics; D000073979:F-Box-WD Repeat-Containing Protein 7; D018628:Gene Dosage; D015321:Gene Rearrangement; D015894:Genome, Human; D018398:Homeodomain Proteins / Q000235:genetics*; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D015459:Leukemia-Lymphoma, Adult T-Cell / Q000235:genetics*; D017384:Sequence Deletion; D044767:Ubiquitin-Protein Ligases / Q000235:genetics; D025721:WT1 Proteins / Q000235:genetics
chemical_list: D018797:Cell Cycle Proteins; D044783:F-Box Proteins; D000073979:F-Box-WD Repeat-Containing Protein 7; C513273:FBXW7 protein, human; D018398:Homeodomain Proteins; C489494:TLX3 protein, human; D025721:WT1 Proteins; D044767:Ubiquitin-Protein Ligases