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.
Highlights
Leukemia consists of a broad diagnostic category of hematological malignancies that are estimated to account for over 52,000 new cancer diagnoses in the United States, resulting in over 24,000 deaths annually [1]
We demonstrate that direct cell-cell communication between leukemia cells occurs, in part due to a Cx25-dependent mechanism that enables enhanced tumor cell proliferation and allows for the identification of additional potential specific gap junction protein functions as targets for anti-tumor therapy
To assess whether direct cell-cell communication was present in leukemia cells, we used several cell lines to model both acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML) (Figure 1A-1D)
Summary
Leukemia consists of a broad diagnostic category of hematological malignancies that are estimated to account for over 52,000 new cancer diagnoses in the United States, resulting in over 24,000 deaths annually [1]. In the close confines of the bone marrow, cellcell and cell-ECM communication plays a large role in promoting hematopoietic progenitor cell (HPC) survival, expansion, and differentiation [5]. These interactions are thought to be essential for the tumorigenesis and progression of leukemia. We demonstrate that direct cell-cell communication between leukemia cells occurs, in part due to a Cx25-dependent mechanism that enables enhanced tumor cell proliferation and allows for the identification of additional potential specific gap junction protein functions as targets for anti-tumor therapy
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