title: The t(X;7)(q22;q34) in paediatric T-cell acute lymphoblastic leukaemia results in overexpression of the insulin receptor substrate 4 gene through illegitimate recombination with the T-cell receptor beta locus.
abstract: The t(X;7)(q22;q34), a translocation not previously reported in a neoplastic disorder, was identified and molecularly characterised in a paediatric T-cell acute lymphoblastic leukaemia (T-ALL), subsequently shown also to harbour a deletion of 6q, a STIL/TAL1 fusion and an activating NOTCH1 mutation. The t(X;7) was further investigated using fluorescence in situ hybridisation (FISH), real-time quantitative polymerase chain reaction (RQ-PCR) and Western blot analyses. FISH revealed a breakpoint at the T-cell receptor beta locus at 7q34 and mapped the corresponding breakpoint to Xq22.3. The latter region contains only two known genes, namely insulin receptor substrate 4 (IRS4) and collagen, type IV, alpha 5 (COL4A5), the expressions of which were analysed by the use of RQ-PCR. COL4A5 was not differentially expressed in the t(X;7)-positive sample compared to five T-ALL controls. However, a marked, 1000-fold overexpression of IRS4 was identified. Western blot analysis with a monoclonal antibody against IRS4 showed overexpression also at the protein level. Considering that forced expression of several members of the IRS family has been shown to result in increased cell proliferation, for example in haematopoietic cells, we hypothesise that the IRS4 up-regulation in T-ALL is pathogenetically important as a mitogenic stimulus.
authors.affiliation: Department of Clinical Genetics, Lund University Hospital, Lund, Sweden. kristina.karrman@med.lu.se
authors.forename: Kristina
authors.initials: K
authors.lastname: Karrman
authors.forename: Eigil
authors.initials: E
authors.lastname: Kjeldsen
authors.forename: Carin
authors.initials: C
authors.lastname: Lassen
authors.forename: Margareth
authors.initials: M
authors.lastname: Isaksson
authors.forename: Josef
authors.initials: J
authors.lastname: Davidsson
authors.forename: Anna
authors.initials: A
authors.lastname: Andersson
authors.forename: Henrik
authors.initials: H
authors.lastname: Hasle
authors.forename: Thoas
authors.initials: T
authors.lastname: Fioretos
authors.forename: Bertil
authors.initials: B
authors.lastname: Johansson
mesh_terms: D002648:Child; D002897:Chromosomes, Human, Pair 7 / Q000235:genetics*; D041321:Chromosomes, Human, X / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D055504:Insulin Receptor Substrate Proteins / Q000096:biosynthesis / Q000235:genetics*; D008297:Male; D054218:Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics*; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000235:genetics; D011995:Recombination, Genetic; D014178:Translocation, Genetic; D015854:Up-Regulation
chemical_list: D055504:Insulin Receptor Substrate Proteins; D016693:Receptors, Antigen, T-Cell, alpha-beta