Cassaro, A, Grillo, G, Esposito, I, Reda, G, Cairoli, R, Beghini, A, Notaro, M, Gliozzo, J, Trojani, A, Valentini, G and Di Camillo, B (2021) FZD6 triggers Wnt–signalling driven by WNT10BIVS1 expression and highlights new targets in T cell acute lymphoblastic leukemia. Hematological oncology. ISSN 1099-1069

Abstract

Wnt/Fzd signaling has been implicated in hematopoietic stem cell maintenance and in acute
leukemia establishment. In our previous work we described a recurrent rearrangement involving the
WNT10B locus (WNT10BR), characterized by the expression of WNT10BIVS1 transcript variant, in
acute myeloid leukemia. To determine the occurrence of WNT10BR in T-cell acute lymphoblastic
leukemia (T-ALL), we retrospectively analysed an Italian cohort of patients (n=20) and detected a
high incidence (13/20) of WNT10BIVS1 expression. To address genes involved in WNT10B
molecular response, we have designed a Wnt targeted RNA sequencing panel. Identifying Wnt
agonists and antagonists, it results that the expression of FZD6, LRP5, and PROM1 genes stands
out in WNT10BIVS1 positive patients compared to negative ones. Using MOLT4 and MUTZ-2 as
leukemic cell models, which are characterized by the expression of WNT10BIVS1, we have observed
that WNT10B drives major Wnt activation to the FZD6 receptor complex through receipt of ligand.
Additionally, short hairpin RNAs (shRNAs)-mediated gene silencing and small molecules-mediated
inhibition of WNTs secretion, have been observed to interfere with the WNT10B/FZD6 interaction.
We have therefore identified that WNT10BIVS1 knockdown, or pharmacological interference by the
LGK974 porcupine (PORCN) inhibitor, reduces WNT10B/FZD6 protein complex formation and
significantly impairs intracellular effectors and leukemic expansion. These results describe the
molecular circuit induced by WNT10B and suggest WNT10B/FZD6 as a new target in the T-ALL
treatment strategy.

Item Type:	Article
Keywords:	Wnt signaling, T-ALL, FZD6, WNT10B, porcupine inhibitor, LGK974
Date Deposited:	25 Mar 2021 00:45
Last Modified:	25 Mar 2021 00:45
URI:	https://oak.novartis.com/id/eprint/43799