title: Frequent and sex-biased deletion of SLX4IP by illegitimate V(D)J-mediated recombination in childhood acute lymphoblastic leukemia.
abstract: Acute lymphoblastic leukemia (ALL) accounts for ∼25% of pediatric malignancies. Of interest, the incidence of ALL is observed ∼20% higher in males relative to females. The mechanism behind the phenomenon of sex-specific differences is presently not understood. Employing genome-wide genetic aberration screening in 19 ALL samples, one of the most recurrent lesions identified was monoallelic deletion of the 5' region of SLX4IP. We characterized this deletion by conventional molecular genetic techniques and analyzed its interrelationships with biological and clinical characteristics using specimens and data from 993 pediatric patients enrolled into trial AIEOP-BFM ALL 2000. Deletion of SLX4IP was detected in ∼30% of patients. Breakpoints within SLX4IP were defined to recurrent positions and revealed junctions with typical characteristics of illegitimate V(D)J-mediated recombination. In initial and validation analyses, SLX4IP deletions were significantly associated with male gender and ETV6/RUNX1-rearranged ALL (both overall P < 0.0001). For mechanistic validation, a second recurrent deletion affecting TAL1 and caused by the same molecular mechanism was analyzed in 1149 T-cell ALL patients. Validating a differential role by sex of illegitimate V(D)J-mediated recombination at the TAL1 locus, 128 out of 1149 T-cell ALL samples bore a deletion and males were significantly more often affected (P = 0.002). The repeatedly detected association of SLX4IP deletion with male sex and the extension of the sex bias to deletion of the TAL1 locus suggest that differential illegitimate V(D)J-mediated recombination events at specific loci may contribute to the consistent observation of higher incidence rates of childhood ALL in boys compared with girls.
authors.affiliation: Department of Pediatrics, University Hospital Schleswig-Holstein, Kiel, Germany.
authors.forename: Barbara
authors.initials: B
authors.lastname: Meissner
authors.forename: Thies
authors.initials: T
authors.lastname: Bartram
authors.forename: Cornelia
authors.initials: C
authors.lastname: Eckert
authors.forename: Jan
authors.initials: J
authors.lastname: Trka
authors.forename: Renate
authors.initials: R
authors.lastname: Panzer-Grümayer
authors.forename: Ivana
authors.initials: I
authors.lastname: Hermanova
authors.forename: Eva
authors.initials: E
authors.lastname: Ellinghaus
authors.forename: Andre
authors.initials: A
authors.lastname: Franke
authors.forename: Anja
authors.initials: A
authors.lastname: Möricke
authors.forename: André
authors.initials: A
authors.lastname: Schrauder
authors.forename: Andrea
authors.initials: A
authors.lastname: Teigler-Schlegel
authors.forename: Petra
authors.initials: P
authors.lastname: Dörge
authors.forename: Arend
authors.initials: A
authors.lastname: von Stackelberg
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Basso
authors.forename: Claus R
authors.initials: CR
authors.lastname: Bartram
authors.forename: Renate
authors.initials: R
authors.lastname: Kirschner-Schwabe
authors.forename: Beat
authors.initials: B
authors.lastname: Bornhäuser
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Bourquin
authors.forename: Giovanni
authors.initials: G
authors.lastname: Cazzaniga
authors.forename: Julia
authors.initials: J
authors.lastname: Hauer
authors.forename: Andishe
authors.initials: A
authors.lastname: Attarbaschi
authors.forename: Shai
authors.initials: S
authors.lastname: Izraeli
authors.forename: Marketa
authors.initials: M
authors.lastname: Zaliova
authors.forename: Gunnar
authors.initials: G
authors.lastname: Cario
authors.forename: Martin
authors.initials: M
authors.lastname: Zimmermann
authors.forename: Smadar
authors.initials: S
authors.lastname: Avigad
authors.forename: Magdalena
authors.initials: M
authors.lastname: Sokalska-Duhme
authors.forename: Markus
authors.initials: M
authors.lastname: Metzler
authors.forename: Martin
authors.initials: M
authors.lastname: Schrappe
authors.forename: Rolf
authors.initials: R
authors.lastname: Koehler
authors.forename: Geertruy
authors.initials: G
authors.lastname: Te Kronnie
authors.forename: Martin
authors.initials: M
authors.lastname: Stanulla
mesh_terms: D000293:Adolescent; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics; D002352:Carrier Proteins / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D050676:Core Binding Factor Alpha 2 Subunit / Q000235:genetics; D005260:Female; D017353:Gene Deletion; D006801:Humans; D007223:Infant; D008297:Male; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics*; D011518:Proto-Oncogene Proteins / Q000235:genetics; D050783:Proto-Oncogene Proteins c-ets / Q000235:genetics; D045522:Recombinases / Q000235:genetics*; D012097:Repressor Proteins / Q000235:genetics; D000073942:T-Cell Acute Lymphocytic Leukemia Protein 1; D060152:V(D)J Recombination; D000097764:ETS Translocation Variant 6 Protein
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D002352:Carrier Proteins; D050676:Core Binding Factor Alpha 2 Subunit; D011518:Proto-Oncogene Proteins; D050783:Proto-Oncogene Proteins c-ets; D045522:Recombinases; D012097:Repressor Proteins; D000073942:T-Cell Acute Lymphocytic Leukemia Protein 1; D000097764:ETS Translocation Variant 6 Protein; C493728:RUNX1 protein, human; C000592625:SLX4IP protein, human; C067143:TAL1 protein, human; C542319:SLX4 protein, human