AI Article Synopsis

  • * Researchers found that blocking gap junctions, which facilitate communication between BM-MSCs and leukemic cells, could alter these interactions and potentially reduce chemoresistance in AML.
  • * The gap junction disruptor carbenoxolone (CBX) showed promise as a treatment, demonstrating an ability to induce cell death in AML cells without harming normal progenitor cells, and enhancing the effectiveness of the chemotherapy drug cytarabine.

Article 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.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7002301PMC
http://dx.doi.org/10.1038/s41388-019-1069-yDOI Listing

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