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Birc6 drives drug resistance and cell survival in chronic myeloid leukemia (1055.6)
Author(s) -
Okumu Denis,
Levine Merlin,
Jones Lauren,
Zhang Raymond,
Graves Lee
Publication year - 2014
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.28.1_supplement.1055.6
Subject(s) - lyn , stat5 , gene knockdown , cancer research , k562 cells , myeloid leukemia , tyrosine kinase , imatinib , chemistry , small hairpin rna , leukemia , apoptosis , biology , microbiology and biotechnology , signal transduction , immunology , biochemistry
BIRC6 is a member of the inhibitors of apoptosis proteins (IAPs), a family of functionally and structurally related endogenous proteins known to inhibit apoptosis. High levels of BIRC6 have been reported in various cancer cells. However, little is known about the mechanism of its regulation. We examined BIRC6 expression and how it correlates with drug resistance in Imatinib‐resistant MYL‐R, MYL, and K562 chronic myeloid leukemia (CML) cells. These cell lines are characterized by the increased tyrosine‐kinase activity of Lyn and BCR‐ABL, respectively. Inhibiting Lyn using Dasatinib significantly reduced BIRC6 mRNA and protein expression. Because STAT5 phosphorylation was elevated in MYL‐R cells, we tested the effects of STAT5 knockdown in these cells. STAT5 knockdown reduced the expression of BIRC6 in MYL‐R cells. Additionally, treating K562 or MYL‐R cells with the STAT5 inhibitor pimozide produced similar results, suggesting that STAT5 is an intermediary in the signaling pathway initiated by Lyn or BCR‐ABL. Transfecting K562 and MYL‐R cells with BIRC6 shRNA significantly decreased BIRC6 protein expression. Importantly, treating BIRC6 knockdown cells with imatinib resulted in a large increase in caspase‐3 activation and cell death. Our data suggest that BIRC6 plays an important role in mediating drug resistance and may be a novel and promising STAT5‐ regulated target in CML and other cancers. Grant Funding Source : NIH