TY - JOUR
T1 - Disruption of gap junctions attenuates acute myeloid leukemia chemoresistance induced by bone marrow mesenchymal stromal cells
AU - Kouzi, Farah
AU - Zibara, Kazem
AU - Bourgeais, Jerome
AU - Picou, Frederic
AU - Gallay, Nathalie
AU - Brossaud, Julie
AU - Dakik, Hassan
AU - Roux, Benjamin
AU - Hamard, Sophie
AU - Le Nail, Louis Romee
AU - Hleihel, Rita
AU - Foucault, Amelie
AU - Ravalet, Noemie
AU - Rouleux-Bonnin, Florence
AU - Gouilleux, Fabrice
AU - Mazurier, Frederic
AU - Bene, Marie C.
AU - Akl, Haidar
AU - Gyan, Emmanuel
AU - Domenech, Jorge
AU - El-Sabban, Marwan
AU - Herault, Olivier
N1 - Publisher Copyright:
© 2019, The Author(s).
PY - 2020/2/6
Y1 - 2020/2/6
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85074600127&partnerID=8YFLogxK
U2 - 10.1038/s41388-019-1069-y
DO - 10.1038/s41388-019-1069-y
M3 - Article
C2 - 31649334
AN - SCOPUS:85074600127
SN - 0950-9232
VL - 39
SP - 1198
EP - 1212
JO - Oncogene
JF - Oncogene
IS - 6
ER -