Disruption of gap junctions attenuates acute myeloid leukemia chemoresistance induced by bone marrow mesenchymal stromal cells

• Published in: Oncogene Vol. 39; no. 6; pp. 1198 - 1212
• Main Authors: Kouzi, Farah, Zibara, Kazem, Bourgeais, Jerome, Picou, Frederic, Gallay, Nathalie, Brossaud, Julie, Dakik, Hassan, Roux, Benjamin, Hamard, Sophie, Le Nail, Louis-Romee, Hleihel, Rita, Foucault, Amelie, Ravalet, Noemie, Rouleux-Bonnin, Florence, Gouilleux, Fabrice, Mazurier, Frederic, Bene, Marie C., Akl, Haidar, Gyan, Emmanuel, Domenech, Jorge, El-Sabban, Marwan, Herault, Olivier
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 06.02.2020; Nature Publishing Group; Nature Publishing Group [1987-....]
• Subjects: 13/31; 38/1; 38/90; 631/67/1990/283/1897; 631/67/327; 64/60; Acute myeloid leukemia; Animals; Anti-Ulcer Agents - pharmacology; Antimetabolites, Antineoplastic - pharmacology; Apoptosis; Bone marrow; Cancer; Carbenoxolone - pharmacology; Care and treatment; CD34 antigen; Cell Biology; Cell interactions; Cell Proliferation; Cellular Biology; Chemoresistance; Comparative analysis; Connexins; Cytarabine; Cytarabine - pharmacology; Drug Resistance, Neoplasm; Drug Therapy, Combination; Energy metabolism; Gap junctions; Gap Junctions - drug effects; Hemopoiesis; Human Genetics; Humans; Instrument industry; Internal Medicine; Leukemia; Leukemia, Myeloid, Acute - drug therapy; Leukemia, Myeloid, Acute - metabolism; Leukemia, Myeloid, Acute - pathology; Life Sciences; Medicine; Medicine & Public Health; Mesenchymal stem cells; Mesenchymal Stem Cells - cytology; Mesenchyme; Mice; Mice, Inbred NOD; Mice, SCID; Myeloid leukemia; Oncology; Physiological aspects; Progenitor cells; Stem cells; Stromal cells; Tumor Cells, Cultured; Tumor Microenvironment - drug effects; Xenograft Model Antitumor Assays; Lebanon; United Kingdom; France; United States; Acute myeloid leukaemia; Cancer microenvironment
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/s41388-019-1069-y

The bone marrow (BM) niche impacts the progression of acute myeloid leukemia (AML) by favoring the chemoresistance of AML cells. Intimate interactions between leukemic cells and BM mesenchymal stromal cells (BM-MSCs) play key roles in this process. Direct intercellular communications between hematopoietic cells and BM-MSCs involve connexins, components of gap junctions. We postulated that blocking gap junction assembly could modify cell–cell interactions in the leukemic niche and consequently the chemoresistance. The comparison of BM-MSCs from AML patients and healthy donors revealed a specific profile of connexins in BM-MSCs of the leukemic niche and the effects of carbenoxolone (CBX), a gap junction disruptor, were evaluated on AML cells. CBX presents an antileukemic effect without affecting normal BM-CD34 + progenitor cells. The proapoptotic effect of CBX on AML cells is in line with the extinction of energy metabolism. CBX acts synergistically with cytarabine (Ara-C) in vitro and in vivo. Coculture experiments of AML cells with BM-MSCs revealed that CBX neutralizes the protective effect of the niche against the Ara-C-induced apoptosis of leukemic cells. Altogether, these results suggest that CBX could be of therapeutic interest to reduce the chemoresistance favored by the leukemic niche, by targeting gap junctions, without affecting normal hematopoiesis.