title: Enhanced targeting of CML stem and progenitor cells by inhibition of porcupine acyltransferase in combination with TKI.
abstract: 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 theO-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.
authors.affiliation: Division of Hematology and Oncology, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL.
authors.forename: Puneet
authors.initials: P
authors.lastname: Agarwal
authors.affiliation: Division of Hematopoietic Stem Cell and Leukemia Research, City of Hope National Medical Center, Duarte, CA.
authors.forename: Bin
authors.initials: B
authors.lastname: Zhang
authors.affiliation: Division of Hematopoietic Stem Cell and Leukemia Research, City of Hope National Medical Center, Duarte, CA.
authors.forename: Yinwei
authors.initials: Y
authors.lastname: Ho
authors.affiliation: Division of Hematopoietic Stem Cell and Leukemia Research, City of Hope National Medical Center, Duarte, CA.
authors.forename: Amy
authors.initials: A
authors.lastname: Cook
authors.affiliation: Division of Hematopoietic Stem Cell and Leukemia Research, City of Hope National Medical Center, Duarte, CA.
authors.forename: Ling
authors.initials: L
authors.lastname: Li
authors.affiliation: Department of Genetics, University of Alabama at Birmingham, Birmingham, AL; and.
authors.forename: Fady M
authors.initials: FM
authors.lastname: Mikhail
authors.affiliation: Oncology Disease Area, Novartis Institute of Biomedical Research, Cambridge, MA.
authors.forename: Youzhen
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Oncology Disease Area, Novartis Institute of Biomedical Research, Cambridge, MA.
authors.forename: Margaret E
authors.initials: ME
authors.lastname: McLaughlin
authors.affiliation: Division of Hematology and Oncology, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL.
authors.forename: Ravi
authors.initials: R
authors.lastname: Bhatia
mesh_terms: D000217:Acyltransferases; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects*; D002478:Cells, Cultured; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D006801:Humans; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D008565:Membrane Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008822:Mice, Transgenic; D014411:Neoplastic Stem Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011743:Pyrimidines / Q000494:pharmacology / Q000627:therapeutic use; D014407:Tumor Cells, Cultured; D060449:Wnt Signaling Pathway / Q000187:drug effects
chemical_list: D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D008565:Membrane Proteins; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D000217:Acyltransferases; C491188:PORCN protein, human; D011505:Protein-Tyrosine Kinases; C498826:nilotinib