Cx25 contributes to leukemia cell communication and chemosensitivity
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Maksim Sinyuk1,2, Alvaro G. Alvarado1,3, Pavel Nesmiyanov4, Jeremy Shaw1, Erin E. Mulkearns-Hubert1, Jennifer T. Eurich1, James S. Hale1, Anna Bogdanova4, Masahiro Hitomi1,3, Jaroslaw Maciejewski3,5,6, Alex Y. Huang6,7, Yogen Saunthararajah3,5,6 and Justin D. Lathia1,2,3,6
1 Department of Cellular and Molecular Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA
2 Department of Biological, Geological, and Environmental Sciences, Cleveland State University, Cleveland, OH, USA
3 Department of Molecular Medicine, Lerner College of Medicine, Case Western University, Cleveland, OH, USA
4 Department of Immunology and Allergy, Volgograd State Medical University, Volgograd, Russia
5 Department of Translational Hematology and Oncology Research, Cleveland Clinic, Cleveland, OH, USA
6 Case Comprehensive Cancer Center, Case Western University, Cleveland, OH, USA
7 Department of Pediatrics, Case Western Reserve University, Cleveland, OH, USA
Justin D. Lathia, email:
Keywords: leukemia, gap junctions, Connexin 25, cell-cell communication
Received: June 08, 2015 Accepted: August 11, 2015 Published: August 19, 2015
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.
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