PMID- 33497493
OWN - NLM
STAT- MEDLINE
DCOM- 20210817
LR  - 20210929
IS  - 1099-1069 (Electronic)
IS  - 0278-0232 (Print)
IS  - 0278-0232 (Linking)
VI  - 39
IP  - 3
DP  - 2021 Aug
TI  - FZD6 triggers Wnt-signalling driven by WNT10B(IVS1) expression and highlights new 
      targets in T-cell acute lymphoblastic leukemia.
PG  - 364-379
LID - 10.1002/hon.2840 [doi]
AB  - 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 (WNT10B(R) ), characterized by the 
      expression of WNT10B(IVS1) transcript variant, in acute myeloid leukemia. To 
      determine the occurrence of WNT10B(R) 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 WNT10B(IVS1) 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 WNT10B(IVS1) positive 
      patients compared to negative ones. Using MOLT4 and MUTZ-2 as leukemic cell 
      models, which are characterized by the expression of WNT10B(IVS1) , 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 WNT10B(IVS1) 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.
CI  - (c) 2021 The Authors. Hematological Oncology published by John Wiley & Sons Ltd.
FAU - Cassaro, Adriana
AU  - Cassaro A
AD  - Department of Health Sciences, University of Milan, Milan, Italy.
AD  - Department of Oncology, Hematology Unit, Niguarda Hospital, Milan, Italy.
FAU - Grillo, Giovanni
AU  - Grillo G
AD  - Department of Oncology, Hematology Unit, Niguarda Hospital, Milan, Italy.
FAU - Notaro, Marco
AU  - Notaro M
AD  - Department of Computer Science "Giovanni degli Antoni", University of Milan, 
      Milan, Italy.
FAU - Gliozzo, Jessica
AU  - Gliozzo J
AD  - Department of Computer Science "Giovanni degli Antoni", University of Milan, 
      Milan, Italy.
FAU - Esposito, Ilaria
AU  - Esposito I
AD  - Department of Health Sciences, University of Milan, Milan, Italy.
FAU - Reda, Gianluigi
AU  - Reda G
AD  - Department of Oncology, Hematology Unit, Ospedale Maggiore Policlinico, Milan, 
      Italy.
FAU - Trojani, Alessandra
AU  - Trojani A
AD  - Department of Oncology, Hematology Unit, Niguarda Hospital, Milan, Italy.
FAU - Valentini, Giorgio
AU  - Valentini G
AD  - Department of Computer Science "Giovanni degli Antoni", University of Milan, 
      Milan, Italy.
FAU - Di Camillo, Barbara
AU  - Di Camillo B
AD  - Information Engineering Department, University of Padova, Padova, Italy.
FAU - Cairoli, Roberto
AU  - Cairoli R
AD  - Department of Oncology, Hematology Unit, Niguarda Hospital, Milan, Italy.
FAU - Beghini, Alessandro
AU  - Beghini A
AUID- ORCID: 0000-0002-8234-3474
AD  - Department of Health Sciences, University of Milan, Milan, Italy.
LA  - eng
GR  - FRRB 2015/Fondazione Regionale per la Ricerca Biomedica/
GR  - 2017/Novartis Pharma/
GR  - LGK974 Drug Supply/
GR  - 2017/Lions Club Milano Host/
PT  - Journal Article
DEP - 20210216
PL  - England
TA  - Hematol Oncol
JT  - Hematological oncology
JID - 8307268
RN  - 0 (FZD6 protein, human)
RN  - 0 (Frizzled Receptors)
RN  - 0 (Membrane Proteins)
RN  - 0 (Proto-Oncogene Proteins)
RN  - 0 (Pyrazines)
RN  - 0 (Pyridines)
RN  - 0 (WNT10B protein, human)
RN  - 0 (Wnt Proteins)
RN  - EC 2.3.- (Acyltransferases)
RN  - EC 2.3.1.- (PORCN protein, human)
RN  - U27F40013Q (LGK974)
SB  - IM
MH  - Acyltransferases/antagonists & inhibitors/genetics/metabolism
MH  - Female
MH  - Frizzled Receptors/genetics/*metabolism
MH  - *Gene Expression Regulation, Leukemic
MH  - HeLa Cells
MH  - Humans
MH  - Male
MH  - Membrane Proteins/antagonists & inhibitors/genetics/metabolism
MH  - Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/drug 
      therapy/genetics/*metabolism/pathology
MH  - Proto-Oncogene Proteins/*biosynthesis/genetics
MH  - Pyrazines/pharmacology
MH  - Pyridines/pharmacology
MH  - Wnt Proteins/*biosynthesis/genetics
MH  - *Wnt Signaling Pathway
PMC - PMC8451758
OTO - NOTNLM
OT  - FZD6
OT  - LGK974
OT  - T-ALL
OT  - WNT10B
OT  - Wnt signaling
OT  - porcupine inhibitor
COIS- The authors declare no conflict of interest. The funders had no role in the 
      design of the study; in the collection, analyses, or interpretation of data; in 
      the writing of the manuscript or in the decision to publish the results.
EDAT- 2021/01/27 06:00
MHDA- 2021/08/18 06:00
PMCR- 2021/09/20
CRDT- 2021/01/26 17:11
PHST- 2021/01/20 00:00 [revised]
PHST- 2021/01/13 00:00 [received]
PHST- 2021/01/21 00:00 [accepted]
PHST- 2021/01/27 06:00 [pubmed]
PHST- 2021/08/18 06:00 [medline]
PHST- 2021/01/26 17:11 [entrez]
PHST- 2021/09/20 00:00 [pmc-release]
AID - HON2840 [pii]
AID - 10.1002/hon.2840 [doi]
PST - ppublish
SO  - Hematol Oncol. 2021 Aug;39(3):364-379. doi: 10.1002/hon.2840. Epub 2021 Feb 16.