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Previously, we showed an abundance of inactive GSK\u20103 in the human chronic myeloid leukemia (CML) cell line. CML is a hematopoietic malignancy caused by an oncogenic Bcr\u2010Abl tyrosine kinase. In Bcr\u2010Abl signaling, the role of GSK\u20103 is not well defined. Here, we report that enforced expression of constitutively active GSK\u20103 reduced proliferation and increased Bcr\u2010Abl inhibition\u2010induced apoptosis by nearly 1\u2010fold. Bcr\u2010Abl inhibition activated GSK\u20103 and GSK\u20103\u2010dependent apoptosis. Inactivation of GSK\u20103 by Bcr\u2010Abl activity is, therefore, confirmed. To reactivate GSK\u20103, we used glucosylceramide synthase (GCS) inhibitor PDMP to accumulate endogenous ceramide, a tumor\u2010suppressor sphingo\u2010lipid and a potent GSK\u20103 activator. We found that either PDMP or silence of GCS increased Bcr\u2010Abl inhibition\u2010induced GSK\u20103 activation and apoptosis. Furthermore, PDMP sensitized the most clinical problematic drug\u2010resistant CML T315I mutant to Bcr\u2010Abl inhibitor GNF\u20102\u2010, imatinib\u2010, or nilotinib\u2010induced apoptosis by &gt;5\u2010fold. Combining PDMP and GNF\u20102 eliminated transplanted\u2010CML\u2010T315I\u2010mutants\n                    <jats:italic>in vivo<\/jats:italic>\n                    and dose dependently sensitized primary cells from CML T315I patients to GNF\u20102\u2010induced proliferation inhibition and apoptosis. The synergistic efficacy was Bcr\u2010Abl restricted and correlated to increased intracellular ceramide levels and acted through GSK\u20103\u2010mediated apoptosis. This study suggests a feasible novel anti\u2010CML strategy by accumulating endogenous ceramide to reactivate GSK\u20103 and abrogate drug resistance.\u2014Huang, W.\u2010C., Tsai, C.\u2010C., Chen, C.\u2010L., Chen, T.\u2010Y., Chen, Y.\u2010P., Lin, Y.\u2010S., Lu, P.\u2010J., Lin, C.\u2010M., Wang, S.\u2010W., Tsao, C.\u2010W., Wang, C.\u2010Y., Cheng, Y.\u2010L., Hsieh, C.\u2010Y., Tseng, P.\u2010C., Lin, C.\u2010F. Glucosylceramide synthase inhibitor PDMP sensitizes chronic myeloid leukemia T315I mutant to Bcr\u2010Abl inhibitor and cooperatively induces glycogen synthase kinase\u20103\u2010regulated apoptosis.\n                    <jats:italic>FASEB J.<\/jats:italic>\n                    25, 3661\u20133673 (2011).\n                    <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"http:\/\/www.fasebj.org\">www.fasebj.org<\/jats:ext-link>\n                  <\/jats:p>","DOI":"10.1096\/fj.10-180190","type":"journal-article","created":{"date-parts":[[2011,6,25]],"date-time":"2011-06-25T01:31:43Z","timestamp":1308965503000},"page":"3661-3673","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":35,"title":["Glucosylceramide synthase inhibitor PDMP sensitizes chronic myeloid leukemia T315I mutant to Bcr\u2010Abl inhibitor and cooperatively induces glycogen synthase kinase\u20103\u2010regulated 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