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Stromal CYR 61 Confers Resistance to Mitoxantrone via Spleen Tyrosine Kinase Activation in Human Acute Myeloid Leukaemia
Author(s) -
Long Xin,
Yu Yang,
Perlaky Laszlo,
Man TszKwong,
Redell Michele S.
Publication year - 2015
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.13492
Subject(s) - cancer research , stromal cell , mitoxantrone , syk , stroma , bone marrow , biology , cyr61 , haematopoiesis , medicine , tyrosine kinase , chemotherapy , immunology , signal transduction , microbiology and biotechnology , stem cell , growth factor , receptor , immunohistochemistry , ctgf
Summary Approximately 50% of children with acute myeloid leukaemia ( AML ) relapse, despite aggressive chemotherapy. The bone marrow stromal environment protects leukaemia cells from chemotherapy (i.e., stroma‐induced chemoresistance), eventually leading to recurrence. Our goal is to delineate the mechanisms underlying stroma‐mediated chemoresistance in AML . We used two human bone marrow stromal cell lines, HS ‐5 and HS ‐27A, which are equally effective in protecting AML cells from chemotherapy‐induced apoptosis in AML ‐stromal co‐cultures. We found that CYR 61 was highly expressed by stromal cells, and was upregulated in AML cells by both stromal cell lines. CYR 61 is a secreted matricellular protein and is associated with cell‐intrinsic chemoresistance in other malignancies. Here, we show that blocking stromal CYR 61 activity, by neutralization or RNA i, increased mitoxantrone‐induced apoptosis in AML cells in AML ‐stromal co‐cultures, providing functional evidence for its role in stroma‐mediated chemoresistance. Further, we found that spleen tyrosine kinase ( SYK ) mediates CYR 61 signalling. Exposure to stroma increased SYK expression and activation in AML cells, and this increase required CYR 61. SYK inhibition reduced stroma‐dependent mitoxantrone resistance in the presence of CYR 61, but not in its absence. Therefore, SYK is downstream of CYR 61 and contributes to CYR 61‐mediated mitoxantrone resistance. The CYR 61‐ SYK pathway represents a potential target for reducing stroma‐induced chemoresistance.