Sinyuk Maksim, Alvarado Alvaro G, Nesmiyanov Pavel, Shaw Jeremy, Mulkearns-Hubert Erin E, Eurich Jennifer T, Hale James S, Bogdanova Anna, Hitomi Masahiro, Maciejewski Jaroslaw, Huang Alex Y, Saunthararajah Yogen, Lathia Justin D
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.
Oncotarget. 2015 Oct 13;6(31):31508-21. doi: 10.18632/oncotarget.5226.
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.
白血病包括几种具有共同表型的血液系统恶性肿瘤，这些表型包括快速增殖、白细胞异常自我更新以及随后正常造血功能的破坏。虽然白血病细胞与周围基质之间的通讯支持肿瘤的存活和扩张，但白血病细胞间直接通讯的机制及其对肿瘤生长的作用尚不清楚。间隙连接是由连接蛋白组成的特殊细胞间连接，允许小分子和离子在相邻细胞的细胞质之间直接自由扩散。为了表征同型白血病细胞通讯，我们采用了急性髓系白血病（AML）和急性淋巴细胞白血病（ALL）的体外模型，并通过染料转移试验测量间隙连接功能。此外，还使用了临床相关的间隙连接抑制剂，即甘草次酸（CBX）和1-辛醇，来解除白血病细胞的通讯能力。此外，qRT-PCR筛选显示，与正常造血干细胞相比，白血病细胞中有几种连接蛋白表达更高。Cx25被确定为一个有前景的辅助治疗靶点，通过RNA干扰降低Cx25而非Cx43可减少细胞间通讯并使细胞对化疗敏感。综上所述，我们的数据表明白血病中存在通过Cx25依赖性间隙连接机制的同型通讯，这可用于开发抗白血病疗法。
