Inhibition of Wnt16 in human acute lymphoblastoid leukemia cells containing the t(1;19) translocation induces apoptosis

Abstract

The Wnt family of secreted glycoproteins is widely involved in cell proliferation, differentiation and oncogenesis. Many Wnt signaling genes are upregulated and activated in chronic lymphocytic leukemia. Less is known concerning acute leukemia. One subtype of acute lymphoblastoid leukemia (ALL) is characterized by a t(1;19) chromosomal translocation resulting in a fusion protein E2A-Pbx1 that promotes transformation and leukemogenesis. Wnt16 has been shown to be targeted by E2A-Pbx1. We performed a differential gene expression array in acute leukemia cell lines displaying or not displaying the t(1;19) translocation. We found that Wnt16 and many Wnt signaling-related genes were upregulated in the translocation-containing cells. As two isoforms of Wnt16, Wnt16a and Wnt16b, have been recently identified, we demonstrated by using RT-PCR and Western blot that Wnt16b (and not Wnt16a) is overexpressed in t(1;19)-containing cell lines. We then directly addressed the role played by both isoforms in this type of leukemia. Using specific short interfering RNA (siRNA) and an antiWnt16 antibody, we showed that targeted-Wnt16b inhibition leads to apoptotic cell death. We also demonstrated that Wnt16b mediates its effect through the canonical Wnt pathway involving dishevelled-2, b-catenin and survivin. We thus propose that Wnt16 plays an important role in leukemogenesis, raising its therapeutic interest.

Role for WNT16B in human epidermal keratinocyte proliferation and differentiation

“…Using WNT16 isoform-specific RT-PCR, WNT16B was upregulated in the BCCs compared with normal skin. WNT16B is also upregulated in both chronic lymphocytic leukaemia (Lu et al, 2004) and acute lymphoblastoid leukaemia (Mazieres et al, 2005), which indicates that WNT16B might play a key role in tumourigenesis.…”

The emerging role of Wnt signaling in the pathogenesis of acute myeloid leukemia

“…153 Moreover, blockade of Wnt signaling by either siRNA or use of specific antibodies inhibits tumor growth and induces apoptosis of cancer cells. 153,154 Mazieres et al, 155 could show that inhibition of Wnt16 by the use of siRNA and an anti-Wnt16 antibody induces apoptosis in human ALL cells containing the t(1;19) translocation. Targeted Wnt blockage has to be handled with care to minimize risk for derogations of normal hematopoiesis.…”

Regulation of hematopoiesis and the hematopoietic stem cell niche by Wnt signaling pathways

“…E2A-Pbx1 induces expression of Wnt16b [114]. Wnt16b induces canonical Wnt signaling and inhibition of Wnt16b in ALL cell lines resulted in increased apoptosis [115]. Recently, it was demonstrated that promoters for canonical Wnt pathway inhibitory genes (e.g., sFRP-1, Wif-1, and Dkk-3) were abnormally methylated in ALL samples across a spectrum of genetic lesions [116].…”