title: Cx25 contributes to leukemia cell communication and chemosensitivity.
abstract: Leukemia encompasses several hematological malignancies with shared phenotypes that include rapid proliferation, abnormal leukocyte self-renewal, and subsequent disruption of normal hematopoiesis. While communication between leukemia cells and the surrounding stroma supports tumor survival and expansion, the mechanisms underlying direct leukemia cell-cell communication and its contribution to tumor growth are undefined. Gap junctions are specialized intercellular connections composed of connexin proteins that allow free diffusion of small molecules and ions directly between the cytoplasm of adjacent cells. To characterize homotypic leukemia cell communication, we employed in vitro models for both acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL) and measured gap junction function through dye transfer assays. Additionally, clinically relevant gap junction inhibitors, carbenoxolone (CBX) and 1-octanol, were utilized to uncouple the communicative capability of leukemia cells. Furthermore, a qRT-PCR screen revealed several connexins with higher expression in leukemia cells compared with normal hematopoietic stem cells. Cx25 was identified as a promising adjuvant therapeutic target, and Cx25 but not Cx43 reduction via RNA interference reduced intercellular communication and sensitized cells to chemotherapy. Taken together, our data demonstrate the presence of homotypic communication in leukemia through a Cx25-dependent gap junction mechanism that can be exploited for the development of anti-leukemia therapies.
authors.affiliation: Department of Cellular and Molecular Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA.|Department of Biological, Geological, and Environmental Sciences, Cleveland State University, Cleveland, OH, USA.
authors.forename: Maksim
authors.initials: M
authors.lastname: Sinyuk
authors.affiliation: Department of Cellular and Molecular Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA.|Department of Molecular Medicine, Lerner College of Medicine, Case Western University, Cleveland, OH, USA.
authors.forename: Alvaro G
authors.initials: AG
authors.lastname: Alvarado
authors.affiliation: Department of Immunology and Allergy, Volgograd State Medical University, Volgograd, Russia.
authors.forename: Pavel
authors.initials: P
authors.lastname: Nesmiyanov
authors.affiliation: Department of Cellular and Molecular Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA.
authors.forename: Jeremy
authors.initials: J
authors.lastname: Shaw
authors.affiliation: Department of Cellular and Molecular Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA.
authors.forename: Erin E
authors.initials: EE
authors.lastname: Mulkearns-Hubert
authors.affiliation: Department of Cellular and Molecular Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA.
authors.forename: Jennifer T
authors.initials: JT
authors.lastname: Eurich
authors.affiliation: Department of Cellular and Molecular Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA.
authors.forename: James S
authors.initials: JS
authors.lastname: Hale
authors.affiliation: Department of Immunology and Allergy, Volgograd State Medical University, Volgograd, Russia.
authors.forename: Anna
authors.initials: A
authors.lastname: Bogdanova
authors.affiliation: Department of Cellular and Molecular Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA.|Department of Molecular Medicine, Lerner College of Medicine, Case Western University, Cleveland, OH, USA.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Hitomi
authors.affiliation: Department of Molecular Medicine, Lerner College of Medicine, Case Western University, Cleveland, OH, USA.|Department of Translational Hematology and Oncology Research, Cleveland Clinic, Cleveland, OH, USA.|Case Comprehensive Cancer Center, Case Western University, Cleveland, OH, USA.
authors.forename: Jaroslaw
authors.initials: J
authors.lastname: Maciejewski
authors.affiliation: Case Comprehensive Cancer Center, Case Western University, Cleveland, OH, USA.|Department of Pediatrics, Case Western Reserve University, Cleveland, OH, USA.
authors.forename: Alex Y
authors.initials: AY
authors.lastname: Huang
authors.affiliation: Department of Molecular Medicine, Lerner College of Medicine, Case Western University, Cleveland, OH, USA.|Department of Translational Hematology and Oncology Research, Cleveland Clinic, Cleveland, OH, USA.|Case Comprehensive Cancer Center, Case Western University, Cleveland, OH, USA.
authors.forename: Yogen
authors.initials: Y
authors.lastname: Saunthararajah
authors.affiliation: Department of Cellular and Molecular Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA.|Department of Biological, Geological, and Environmental Sciences, Cleveland State University, Cleveland, OH, USA.|Department of Molecular Medicine, Lerner College of Medicine, Case Western University, Cleveland, OH, USA.|Case Comprehensive Cancer Center, Case Western University, Cleveland, OH, USA.
authors.forename: Justin D
authors.initials: JD
authors.lastname: Lathia
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D002450:Cell Communication / Q000187:drug effects*; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D017630:Connexins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D005455:Fluorescent Antibody Technique; D017629:Gap Junctions / Q000187:drug effects*; D006412:Hematopoietic Stem Cells / Q000187:drug effects; D006801:Humans; D007124:Immunoenzyme Techniques; D019169:Jurkat Cells; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D012333:RNA, Messenger / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D000970:Antineoplastic Agents; D017630:Connexins; C471697:GJB7 protein, human; D012333:RNA, Messenger; D034741:RNA, Small Interfering
keywords: Connexin 25; cell-cell communication; gap junctions; leukemia