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Bone marrow stroma protects myeloma cells from cytotoxic damage via induction of the oncoprotein MUC 1
Author(s) -
BarNatan Michal,
Stroopinsky Dina,
Luptakova Katarina,
Coll Maxwell D.,
Apel Arie,
Rajabi Hasan,
Pyzer Athalia R.,
Palmer Kristen,
Reagan Michaela R.,
Nahas Myrna R.,
Karp Leaf Rebecca,
Jain Salvia,
Arnason Jon,
Ghobrial Irene M.,
Anderson Kenneth C.,
Kufe Donald,
Rosenblatt Jacalyn,
Avigan David
Publication year - 2017
Publication title -
british journal of haematology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.907
H-Index - 186
eISSN - 1365-2141
pISSN - 0007-1048
DOI - 10.1111/bjh.14493
Subject(s) - stromal cell , cytotoxic t cell , bone marrow , cancer research , biology , apoptosis , cell culture , tumor necrosis factor alpha , proinflammatory cytokine , immunology , inflammation , in vitro , biochemistry , genetics
Summary Multiple myeloma ( MM ) is a lethal haematological malignancy that arises in the context of a tumour microenvironment that promotes resistance to apoptosis and immune escape. In the present study, we demonstrate that co‐culture of MM cells with stromal cells results in increased resistance to cytotoxic and biological agents as manifested by decreased rates of cell death following exposure to alkylating agents and the proteosome inhibitor, bortezomib. To identify the mechanism of increased resistance, we examined the effect of the co‐culture of MM cells with stroma cells, on expression of the MUC 1 oncogene, known to confer tumour cells with resistance to apoptosis and necrosis. Co‐culture of stroma with MM cells resulted in increased MUC 1 expression by tumour cells. The effect of stromal cell co‐culture on MUC 1 expression was not dependent on cell contact and was therefore thought to be due to soluble factors secreted by the stromal cells into the microenvironment. We demonstrated that MUC 1 expression was mediated by interleukin‐6 and subsequent up‐regulation of the JAK ‐ STAT pathway. Interestingly, the effect of stromal cell co‐culture on tumour resistance was partially reversed by silencing of MUC 1 in MM cells, consistent with the potential role of MUC 1 in mediating resistance to cytotoxic‐based therapies.