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TGF‐β receptor kinase inhibitor LY2109761 reverses the anti‐apoptotic effects of TGF‐β1 in myelo‐monocytic leukaemic cells co‐cultured with stromal cells
Author(s) -
Xu Yuanyuan,
Tabe Yoko,
Jin Linhua,
Watt Julie,
McQueen Teresa,
Ohsaka Akimichi,
Andreeff Michael,
Konopleva Marina
Publication year - 2008
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/j.1365-2141.2008.07130.x
Subject(s) - stromal cell , cancer research , cell culture , u937 cell , biology , mesenchymal stem cell , bone marrow , transforming growth factor , cell growth , apoptosis , microbiology and biotechnology , immunology , biochemistry , genetics
Summary Transforming growth factor β1 (TGF‐β1) is an essential regulator of cell proliferation, survival and apoptosis, depending on the cellular context. TGF‐β1 is also known to affect cell‐to‐cell interactions between tumour cells and stromal cells. We investigated the role of TGF‐β1 in the survival of myelo‐monocytic leukaemia cell lines co‐cultured with bone marrow (BM)‐derived mesenchymal stem cells (MSC). Treatment with recombinant human (rh)TGF‐β1 inhibited spontaneous and cytarabine‐induced apoptosis in U937 cells, most prominently in U937 cells directly attached to MSCs. Conversely, the pro‐survival effects of TGF‐β1 were inhibited by LY2109761 or TGF‐β1 neutralizing antibody. rhTGF‐β1 increased pro‐survival phosphorylation of Akt, which was inhibited by LY2109761. The combination of rhTGF‐β1 and MSC co‐culture induced significant upregulation of C/EBPβ gene ( CEBPB ) and protein expression along with increased C/EBPβ liver‐enriched activating protein: liver‐enriched inhibitory protein ratio, suggesting the novel role of C/EBPβ in TGF‐β1‐mediated U937 cell survival in the context of stromal cell support. In summary, these results indicate that TGF‐β1 produced by BM stromal cells promotes the survival and chemoresistance of leukaemia cells under the direct cell‐to‐cell interactions. The blockade of TGF‐β signalling by LY2109761, which effectively inhibited the pro‐survival signalling, may enhance the efficacy of chemotherapy against myelo‐monocytic leukaemic cells in the BM microenvironment.