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

Farah Kouzi 1 Kazem Zibara 2 Jerome Bourgeais 1 Frederic Picou 1 Nathalie Gallay 1 Julie Brossaud 3 Hassan Dakik 1 Benjamin Roux 1 Sophie Hamard 1 Louis-Romée Le Nail 4 Rita Hleihel 5 Amelie Foucault 1 Noemie Ravalet 1 Florence Rouleux-Bonnin 6 Fabrice Gouilleux 6 Frédéric Mazurier 6 Marie Béné 7 Haidar Akl 2 Emmanuel Gyan 6 Jorge Domenech 6 Marwan El-Sabban 5 Olivier Herault 6
1 Université de Tours
2 LU - Lebanese University [Beirut]
3 CHU Bordeaux [Bordeaux]
4 CHU Trousseau [Tours]
5 AUB - American University of Beirut [Beyrouth]
6 GICC EA 7501 - Groupe innovation et ciblage cellulaire (GICC), EA 7501 [2018-...]
7 CHU Nantes - Centre hospitalier universitaire de Nantes
Abstract : 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.
Keywords : Acute myeloid leukaemia Cancer microenvironment
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Farah Kouzi, Kazem Zibara, Jerome Bourgeais, Frederic Picou, Nathalie Gallay, et al.. Disruption of gap junctions attenuates acute myeloid leukemia chemoresistance induced by bone marrow mesenchymal stromal cells. Oncogene, Nature Publishing Group, 2019, 39, pp.1198-1212. ⟨10.1038/s41388-019-1069-y⟩. ⟨hal-02411718⟩

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