DNA damage response-initiated cytokine secretion in bone marrow stromal cells promotes chemoresistance of myeloma cells

Acquisition of chemoresistance accounts for a major cause of chemotherapy failure for multiple myeloma (MM). Bone marrow stromal cells (BMSCs) are considered to play a pivotal role in modulating drug resistance of MM cells. However, the underlying mechanism whereby BMSCs, particularly damaged stromal cells, affects chemoresistance has not been identified yet. Here, we show exposure to doxorubicin doxorubicin (Dox) induced dramatic ATM (ataxia-telangiectasia-mutated)-dependent DNA damage response (DDR) and increased secretion of interleukin (IL)-6 in HS-5 cell line and primary BMSCs derived from healthy donors. Specifically, IL-6-containing conditioned media (CM) derived from Dox-pretreated stromal cells displayed significant protective effect on Dox-induced apoptosis of MM cells. Also, treatment of BMSCs with ATM kinase inhibitor markedly reduced IL-6 secretion and concurrently, partially reversed CM-mediated chemoresistance in myeloma cells. These data indicate that DNA-damaging drug triggers an ATM-dependent DDR in BMSCs, leading to increased cytokine secretion and resistance of myeloma cells to chemotherapy-induced apoptosis.