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

被引：34

作者：

Kouzi, Farah ^{[1
,2
,3
]}

Zibara, Kazem ^{[3
,4
]}

Bourgeais, Jerome ^{[1
,2
,5
]}

Picou, Frederic ^{[1
,2
,5
]}

Gallay, Nathalie ^{[1
,2
,5
]}

Brossaud, Julie ^{[6
]}

Dakik, Hassan ^{[1
,2
]}

Roux, Benjamin ^{[1
,2
,5
]}

Hamard, Sophie ^{[1
,2
]}

Le Nail, Louis-Romee ^{[7
]}

Hleihel, Rita ^{[8
,9
]}

Foucault, Amelie ^{[1
,2
,5
]}

Ravalet, Noemie ^{[1
,2
,5
]}

Rouleux-Bonnin, Florence ^{[1
,2
]}

Gouilleux, Fabrice ^{[1
,2
]}

Mazurier, Frederic ^{[1
,2
]}

Bene, Marie C. ^{[10
]}

Akl, Haidar ^{[3
,4
]}

Gyan, Emmanuel ^{[1
,2
,11
]}

Domenech, Jorge ^{[1
,2
,5
]}

El-Sabban, Marwan ^{[8
]}

Herault, Olivier ^{[1
,2
,5
]}

机构：

[1] CNRS, ERL7001, LNOx Leukem Niche & Redox Metab, Tours, France

[2] Univ Tours, Fac Med, EA7501, GICC, Tours, France

[3] Lebanese Univ, DSST, PRASE, Beirut, Lebanon

[4] Lebanese Univ, Fac Sci, Biol Dept, Beirut, Lebanon

[5] Tours Univ Hosp, Dept Biol Hematol, Tours, France

[6] Bordeaux Univ Hosp, Dept Nucl Med, Pessac, France

[7] Tours Univ Hosp, Dept Surg Orthopedia, Tours, France

[8] Amer Univ Beirut, Fac Med, Dept Anat Cell Biol & Physiol Sci, Beirut, Lebanon

[9] Amer Univ Beirut, Fac Med, Dept Internal Med, Beirut, Lebanon

[10] CRCINA, Nantes Univ Hosp, Dept Biol Hematol, Nantes, France

[11] Tours Univ Hosp, Dept Hematol & Cell Therapy, Tours, France

来源：

ONCOGENE | 2020年 / 39卷 / 06期

关键词：

AML CELLS; STEM-CELLS; INCREASE PROLIFERATION; CARBENOXOLONE SODIUM; INHIBIT APOPTOSIS; UP-REGULATION; CONNEXIN-43; EXPRESSION; PROTEIN; IDENTIFICATION;

D O I：

10.1038/s41388-019-1069-y

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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.

引用

页码：1198 / 1212

页数：15

共 62 条

[31] Up-regulation of Cx43 expression and GJIC function in acute leukemia bone marrow stromal cells post-chemotherapy [J].