title: Intronless WNT10B-short variant underlies new recurrent allele-specific rearrangement in acute myeloid leukaemia.
abstract: Defects in the control of Wnt signaling have emerged as a recurrent mechanism involved in cancer pathogenesis and acute myeloid leukaemia (AML), including the hematopoietic regeneration-associated WNT10B in AC133brightleukaemia cells, although the existence of a specific mechanism remains unproven. We have obtained evidences for a recurrent rearrangement, which involved the WNT10B locus (WNT10BR) within intron 1 (IVS1) and flanked at the 5' by non-human sequences whose origin remains to be elucidated; it also expressed a transcript variant (WNT10BIVS1) which was mainly detected in a cohort of patients with intermediate/unfavorable risk AML. We also identified in two separate cases, affected by AML and breast cancer respectively, a genomic transposable short form of human WNT10B (ht-WNT10B). The intronless ht-WNT10B resembles a long non-coding RNA (lncRNA), which suggests its involvement in a non-random microhomology-mediated recombination generating the rearranged WNT10BR. Furthermore, our studies supports an autocrine activation primed by the formation of WNT10B-FZD4/5 complexes in the breast cancer MCF7 cells that express the WNT10BIVS1. Chemical interference of WNT-ligands production by the porcupine inhibitor IWP-2 achieved a dose-dependent suppression of the WNT10B-FZD4/5 interactions. These results present the first evidence for a recurrent rearrangement promoted by a mobile ht-WNT10B oncogene, as a relevant mechanism for Wnt involvement in human cancer.
authors.affiliation: Department of Health Sciences, University of Milan, Milan, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Lazzaroni
authors.affiliation: Department of Biosciences, University of Milan, Milan, Italy.
authors.forename: Luca
authors.initials: L
authors.lastname: Del Giacco
authors.affiliation: Cambridge Institute for Medical Research, University of Cambridge, Cambridge, UK.
authors.forename: Daniele
authors.initials: D
authors.lastname: Biasci
authors.affiliation: Department of Internal Medicine, Valduce Hospital, Como, Italy.
authors.forename: Mauro
authors.initials: M
authors.lastname: Turrini
authors.affiliation: Department of Biosciences, University of Milan, Milan, Italy.
authors.forename: Laura
authors.initials: L
authors.lastname: Prosperi
authors.affiliation: Department of Pathology, Niguarda Hospital, Milan, Italy.
authors.forename: Roberto
authors.initials: R
authors.lastname: Brusamolino
authors.affiliation: Department of Oncology, Hematology Unit, Niguarda Hospital, Milan, Italy.
authors.forename: Roberto
authors.initials: R
authors.lastname: Cairoli
authors.affiliation: Department of Health Sciences, University of Milan, Milan, Italy.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Beghini
mesh_terms: D000818:Animals; D005260:Female; D015973:Gene Expression Regulation, Leukemic; D015321:Gene Rearrangement; D056426:Genetic Loci; D006801:Humans; D007438:Introns; D015470:Leukemia, Myeloid, Acute / Q000235:genetics / Q000378:metabolism; D008297:Male; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis / Q000235:genetics; D051153:Wnt Proteins / Q000096:biosynthesis / Q000235:genetics; D015027:Zebrafish / Q000235:genetics / Q000378:metabolism; D029961:Zebrafish Proteins / Q000096:biosynthesis / Q000235:genetics
chemical_list: D011518:Proto-Oncogene Proteins; C491119:WNT10B protein, human; D051153:Wnt Proteins; D029961:Zebrafish Proteins; C491120:wnt10b protein, zebrafish