FZD6 triggers Wnt–signalling driven by WNT10B^IVS1 expression and highlights new targets in T‐cell acute lymphoblastic leukemia

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.

Circulating microRNAs Suggest Networks Associated with Biological Functions in Aggressive Refractory Type 2 Celiac Disease

“…Again, the functional category GO:0016569 (covalent chromatin modification) includes TET3 and TET2 (Tet methylcytosine dioxygenase 2), with the latter altered in patients with several myeloid malignancies [ 44 , 45 ]; DR1 (the down-regulator of transcription 1), forming the well-known DR1/DRAP1 heterodimer [ 46 ]; and ELK4 (ETS transcription factor ELK4), forming ternary complexes with the serum response elements in the promoter of the c-Fos oncogene [ 47 ]. Interestingly, FZD6 is involved in GO:0198738 (cell–cell signaling by Wnt) [ 48 ] and GO:0002009 (the morphogenesis of an epithelium) [ 49 ], functions that may be strongly associated with CD. Finally, FBXW7 and BTG1 (BTG anti-proliferation factor 1) are linked to chromosomal translocation in B-cell chronic lymphocytic leukemia [ 50 , 51 ], and RORA (RAR related orphan receptor A) has an impact on angiogenesis (GO:0001525) and is crucial for the development of type 2 innate lymphoid cells and cytokine production [ 52 , 53 ].…”

The Prognostic Value of the Developmental Gene FZD6 in Young Saudi Breast Cancer Patients: A Biomarkers Discovery and Cancer Inducers OncoScreen Approach

“…Among the FZD members that have received very little attention in BC is FZD6, despite its important role in other types of cancer including cervical cancer ( Wang et al, 2021 ), colon ( Vincan and Barker, 2008 ; Xu et al, 2019 ), leukaemia ( Wu et al, 2009 ; Yuan et al, 2019 ; Cassaro et al, 2021 ), hepatocarcinoma ( Bengochea et al, 2008 ), squamous cell sarcoma and adenomas ( Haider et al, 2006 ), oral squamous cell carcinoma ( Putnová et al, 2021 ; Sung et al, 2021 ), neuroblastoma ( Cantilena et al, 2011 ), glioblastoma ( Zhang et al, 2021 ), pancreatic adenocarcinoma ( Yang et al, 2019 ; Li et al, 2021 ), and prostate cancer ( Saramäki et al, 2006 ; Han K. et al, 2018 ). Hence, FZD6 was suggested as a promising therapeutic cancer target ( Han K. et al, 2018 ; Zeng et al, 2018 ; Patel et al, 2019 ).…”

KB-68A7.1 Inhibits Hepatocellular Carcinoma Development Through Binding to NSD1 and Suppressing Wnt/β-Catenin Signalling

“…WNT10B is well known to activate Wnt/β-catenin signalling ( 46 , 47 ). Therefore, we further explored the potential effects of KB-68A7.1 on Wnt/β-catenin signalling.…”