PMID- 28011678
OWN - NLM
STAT- MEDLINE
DCOM- 20170817
LR  - 20220114
IS  - 1528-0020 (Electronic)
IS  - 0006-4971 (Print)
IS  - 0006-4971 (Linking)
VI  - 129
IP  - 8
DP  - 2017 Feb 23
TI  - Enhanced targeting of CML stem and progenitor cells by inhibition of porcupine 
      acyltransferase in combination with TKI.
PG  - 1008-1020
LID - 10.1182/blood-2016-05-714089 [doi]
AB  - Tyrosine kinase inhibitor (TKI) treatment of chronic myeloid leukemia (CML) has 
      limited efficacy against leukemia stem cells (LSC) responsible for disease 
      propagation, and most CML patients require continued TKI treatment to maintain 
      remission. LSC maintenance is related, at least in part, to signals from the bone 
      marrow microenvironment (BMM). Our previous studies have shown that Wnt signaling 
      from the BMM contributes to preservation of CML LSC following TKI treatment. 
      Secretion of Wnt ligands requires their modification by the O-acyl transferase 
      Porcupine (PORCN). Here we investigated the activity of a potent and selective 
      PORCN inhibitor, WNT974, against CML stem and progenitor cells. WNT974 
      efficiently antagonized Wnt signaling in human CML CD34(+) cells, and in 
      combination with the TKI nilotinib (NIL) significantly enhanced inhibition of 
      proliferation and colony-forming potential of CML stem and progenitor cells and 
      reduced their growth in immunodeficient mice in vivo, in comparison with NIL 
      alone. Treatment of transgenic CML mice in vivo with NIL in combination with 
      WNT974 significantly reduced leukemic stem and progenitor cell numbers, reduced 
      regeneration of leukemic long-term hematopoietic stem cells in secondary 
      transplant recipients, and enhanced survival of mice after discontinuation of 
      treatment, in comparison with NIL alone. CML progenitors demonstrated enhanced 
      sensitivity to Wnt stimulation, associated with increased expression of the FZD4 
      receptor. FZD4 knockdown inhibited CML progenitor growth. These results support 
      further investigation of PORCN targeting to inhibit Wnt secretion and signaling 
      and enhance targeting of CML stem cells while sparing their normal counterparts.
CI  - (c) 2017 by The American Society of Hematology.
FAU - Agarwal, Puneet
AU  - Agarwal P
AD  - Division of Hematology and Oncology, Department of Medicine, University of 
      Alabama at Birmingham, Birmingham, AL.
FAU - Zhang, Bin
AU  - Zhang B
AD  - Division of Hematopoietic Stem Cell and Leukemia Research, City of Hope National 
      Medical Center, Duarte, CA.
FAU - Ho, Yinwei
AU  - Ho Y
AD  - Division of Hematopoietic Stem Cell and Leukemia Research, City of Hope National 
      Medical Center, Duarte, CA.
FAU - Cook, Amy
AU  - Cook A
AD  - Division of Hematopoietic Stem Cell and Leukemia Research, City of Hope National 
      Medical Center, Duarte, CA.
FAU - Li, Ling
AU  - Li L
AD  - Division of Hematopoietic Stem Cell and Leukemia Research, City of Hope National 
      Medical Center, Duarte, CA.
FAU - Mikhail, Fady M
AU  - Mikhail FM
AD  - Department of Genetics, University of Alabama at Birmingham, Birmingham, AL; and.
FAU - Wang, Youzhen
AU  - Wang Y
AD  - Oncology Disease Area, Novartis Institute of Biomedical Research, Cambridge, MA.
FAU - McLaughlin, Margaret E
AU  - McLaughlin ME
AD  - Oncology Disease Area, Novartis Institute of Biomedical Research, Cambridge, MA.
FAU - Bhatia, Ravi
AU  - Bhatia R
AD  - Division of Hematology and Oncology, Department of Medicine, University of 
      Alabama at Birmingham, Birmingham, AL.
LA  - eng
GR  - P30 CA013148/CA/NCI NIH HHS/United States
GR  - P30 CA033572/CA/NCI NIH HHS/United States
GR  - R01 CA172447/CA/NCI NIH HHS/United States
PT  - Journal Article
DEP - 20161223
PL  - United States
TA  - Blood
JT  - Blood
JID - 7603509
RN  - 0 (Antineoplastic Agents)
RN  - 0 (Enzyme Inhibitors)
RN  - 0 (Membrane Proteins)
RN  - 0 (Protein Kinase Inhibitors)
RN  - 0 (Pyrimidines)
RN  - EC 2.3.- (Acyltransferases)
RN  - EC 2.3.1.- (PORCN protein, human)
RN  - EC 2.7.10.1 (Protein-Tyrosine Kinases)
RN  - F41401512X (nilotinib)
SB  - IM
MH  - Acyltransferases
MH  - Animals
MH  - Antineoplastic Agents/pharmacology/*therapeutic use
MH  - Apoptosis/drug effects
MH  - Cell Proliferation/*drug effects
MH  - Cells, Cultured
MH  - Enzyme Inhibitors/pharmacology/*therapeutic use
MH  - Humans
MH  - Leukemia, Myelogenous, Chronic, BCR-ABL Positive/*drug 
      therapy/metabolism/pathology
MH  - Membrane Proteins/*antagonists & inhibitors/metabolism
MH  - Mice, Transgenic
MH  - Neoplastic Stem Cells/*drug effects/metabolism/pathology
MH  - Protein Kinase Inhibitors/pharmacology/therapeutic use
MH  - Protein-Tyrosine Kinases/*antagonists & inhibitors/metabolism
MH  - Pyrimidines/pharmacology/therapeutic use
MH  - Tumor Cells, Cultured
MH  - Wnt Signaling Pathway/drug effects
PMC - PMC5324714
EDAT- 2016/12/25 06:00
MHDA- 2017/08/18 06:00
PMCR- 2018/02/23
CRDT- 2016/12/25 06:00
PHST- 2016/05/03 00:00 [received]
PHST- 2016/12/16 00:00 [accepted]
PHST- 2016/12/25 06:00 [pubmed]
PHST- 2017/08/18 06:00 [medline]
PHST- 2016/12/25 06:00 [entrez]
PHST- 2018/02/23 00:00 [pmc-release]
AID - S0006-4971(20)33671-5 [pii]
AID - 2016/714089 [pii]
AID - 10.1182/blood-2016-05-714089 [doi]
PST - ppublish
SO  - Blood. 2017 Feb 23;129(8):1008-1020. doi: 10.1182/blood-2016-05-714089. Epub 2016 
      Dec 23.