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 (WNT10B R) 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 (WNT10B IVS1) 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 WNT10B R. 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.
Francesca, L., Luca Del, G., Daniele, B., Mauro, T., Laura, P., Roberto, B., et al. (2016). Intronless WNT10B-short variant underlies new recurrent allele-specific rearrangement in acute myeloid leukaemia. SCIENTIFIC REPORTS, 6, 1-14 [10.1038/srep37201].
Intronless WNT10B-short variant underlies new recurrent allele-specific rearrangement in acute myeloid leukaemia
Cairoli Roberto;
2016
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 (WNT10B R) 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 (WNT10B IVS1) 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 WNT10B R. 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.File | Dimensione | Formato | |
---|---|---|---|
Lazzaroni-2013-Sci Rep-VoR.pdf
accesso aperto
Descrizione: Article
Tipologia di allegato:
Publisher’s Version (Version of Record, VoR)
Licenza:
Creative Commons
Dimensione
1.76 MB
Formato
Adobe PDF
|
1.76 MB | Adobe PDF | Visualizza/Apri |
I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.