FZD6 triggers Wnt–signalling driven by WNT10BIVS1 expression and highlights new targets in T-cell acute lymphoblastic leukemia

Adriana Cassaro, Giovanni Grillo, Marco Notaro, Jessica Gliozzo, Ilaria Esposito, Gianluigi Reda, Alessandra Trojani, Giorgio Valentini, Barbara Di Camillo, Roberto Cairoli, Alessandro Beghini

Research output: Contribution to journalArticlepeer-review

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 analyzed 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 molecule-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.

Original languageEnglish
Pages (from-to)364-379
JournalHematological Oncology
Volume39
Issue number3
DOIs
Publication statusPublished - 2021

Keywords

  • FZD6
  • LGK974
  • porcupine inhibitor
  • T-ALL
  • Wnt signaling
  • WNT10B

ASJC Scopus subject areas

  • Hematology
  • Oncology
  • Cancer Research

Fingerprint

Dive into the research topics of 'FZD6 triggers Wnt–signalling driven by WNT10B<sup>IVS1</sup> expression and highlights new targets in T-cell acute lymphoblastic leukemia'. Together they form a unique fingerprint.

Cite this