title: Polymeric nanoparticle-mediated silencing of CD44 receptor in CD34+ acute myeloid leukemia cells.
abstract: The adhesion receptor CD44 plays an important role in the survival and retention of leukemic stem/progenitor cells (LSPC) within the bone marrow (BM) niche, as well as in the high relapse rates of acute myeloid leukemia (AML). Down-regulating CD44 could be clinically relevant not only for suppression of the deregulated function of LSPC but also in LSPC response to chemotherapeutic agents. Small interfering RNA (siRNA) delivery is a promising approach for AML treatment, and we recently reported effective siRNA delivery into difficult-to-transfect AML cell lines using lipid-substituted polyethylenimine/siRNA complexes (polymeric nanoparticles). In this study, we investigated polymeric nanoparticle-mediated silencing of CD44 in CD34+ LSPC cell models (leukemic KG-1 and KG-1a cell lines) as well as primary AML cells. Polymeric nanoparticle-mediated silencing decreased surface CD44 levels in KG-1, KG-1a and primary AML cells by up to 27%, 30% and 20% at day 3, respectively. Moreover, CD44 silencing resulted in induction of apoptosis in KG-1 cells, reduced adhesion of KG-1 and KG-1a cells to hyaluronic acid-coated cell culture plates and BM-MSC, and decreased adhesion of primary AML cells to BM-MSC. Our results suggest that polymeric nanoparticle-mediated silencing of CD44 might be a useful technique for inhibiting LSPC interactions with their microenvironment, thereby prohibiting leukemia progression or sensitizing LSPC to chemotherapy.
authors.affiliation: Department of Biomedical Engineering, University of Alberta, Edmonton, Alberta, Canada. Electronic address: hilal.gul@ualberta.ca.
authors.forename: Hilal
authors.initials: H
authors.lastname: Gul-Uludağ
authors.affiliation: Department of Biomedical Engineering, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Juliana
authors.initials: J
authors.lastname: Valencia-Serna
authors.affiliation: Department of Biomedical Engineering, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Cezary
authors.initials: C
authors.lastname: Kucharski
authors.affiliation: Canadian Blood Services, Centre for Innovation (Formerly R&D), Edmonton, Alberta, Canada.
authors.forename: Leah A
authors.initials: LA
authors.lastname: Marquez-Curtis
authors.affiliation: Terry Fox Laboratory, British Columbia Cancer Agency, Canada; Department of Medical Genetics, University of British Columbia, Vancouver, BC, Canada.
authors.forename: Xiaoyan
authors.initials: X
authors.lastname: Jiang
authors.affiliation: Department of Medicine, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Loree
authors.initials: L
authors.lastname: Larratt
authors.affiliation: Canadian Blood Services, Centre for Innovation (Formerly R&D), Edmonton, Alberta, Canada; Department of Medicine, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Anna
authors.initials: A
authors.lastname: Janowska-Wieczorek
authors.affiliation: Department of Biomedical Engineering, University of Alberta, Edmonton, Alberta, Canada; Department of Chemical and Materials Engineering, Faculty of Engineering, University of Alberta, Edmonton, Alberta, Canada; Faculty of Pharmacy & Pharmaceutical Sciences, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Hasan
authors.initials: H
authors.lastname: Uludağ
mesh_terms: D018952:Antigens, CD34 / Q000276:immunology*; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D020868:Gene Silencing; D006801:Humans; D018960:Hyaluronan Receptors / Q000378:metabolism*; D015470:Leukemia, Myeloid, Acute / Q000276:immunology* / Q000473:pathology; D053758:Nanoparticles; D016133:Polymerase Chain Reaction; D011108:Polymers / Q000737:chemistry*; D034741:RNA, Small Interfering; D011946:Receptors, Antigen / Q000235:genetics*
chemical_list: D018952:Antigens, CD34; D018960:Hyaluronan Receptors; D011108:Polymers; D034741:RNA, Small Interfering; D011946:Receptors, Antigen
keywords: Acute myeloid leukemia; CD44 receptor; Polymeric nanoparticle; siRNA silencing