1. Intronless WNT10B-short variant underlies new recurrent allele-specific rearrangement in acute myeloid leukaemia
- Author
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Alessandro Beghini, Roberto Cairoli, Roberto Brusamolino, Laura Prosperi, Luca Del Giacco, Mauro Turrini, Francesca Lazzaroni, Daniele Biasci, Francesca, L, Luca Del, G, Daniele, B, Mauro, T, Laura, P, Roberto, B, Cairoli, R, and Alessandro, B
- Subjects
0301 basic medicine ,Male ,Myeloid ,Wnt Protein ,Intron ,Biology ,03 medical and health sciences ,Proto-Oncogene Proteins ,medicine ,Animals ,Humans ,Autocrine signalling ,Zebrafish ,Genetics ,Gene Rearrangement ,Proto-Oncogene Protein ,Multidisciplinary ,Oncogene ,Animal ,Gene Expression Regulation, Leukemic ,Wnt signaling pathway ,Gene rearrangement ,Zebrafish Proteins ,medicine.disease ,Corrigenda ,Introns ,Wnt Proteins ,Leukemia ,Haematopoiesis ,Leukemia, Myeloid, Acute ,030104 developmental biology ,medicine.anatomical_structure ,Genetic Loci ,Female ,Human - 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 AC133bright leukaemia 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.
- Published
- 2016