Expansion of Bcr-Abl-positive leukemic stem cells is dependent on hedgehog pathway activation

被引:447
作者
Dierks, Christine [1 ,2 ,3 ]
Beigi, Ronak [2 ,3 ]
Guo, Gui-Rong [2 ,3 ]
Zirlik, Katja [1 ]
Stegert, Mario R. [2 ,3 ]
Manley, Paul [4 ]
Trussell, Christopher [2 ,3 ]
Schmitt-Graeff, Annette [1 ]
Landwerlin, Klemens [1 ]
Veelken, Hendrik [1 ]
Warmuth, Markus [2 ,3 ,5 ]
机构
[1] Univ Freiburg, Dept Hematol Oncol, D-79106 Freiburg, Germany
[2] Novartis Res Fdn, Genom Inst, Dept Pharmacol, San Diego, CA 92121 USA
[3] Novartis Res Fdn, Genom Inst, Dept Med Chem, San Diego, CA 92121 USA
[4] Novartis Inst BioMed Res, CH-4002 Basel, Switzerland
[5] Novartis Inst BioMed Res, Cambridge, MA 02139 USA
关键词
D O I
10.1016/j.ccr.2008.08.003
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Resistance of Bcr-Abl-positive leukemic stem cells (LSCs) to imatinib treatment in patients with chronic myeloid leukemia (CIVIL) can cause relapse of disease and might be the origin for emerging drug-resistant clones. In this study, we identified Smo as a drug target in Bcr-Abl-positive LSCs. We show that Hedgehog signaling is activated in LSCs through upregulation of Smo. While Smo(-/-) does not impact long-term reconstitution of regular hematopoiesis, the development of retransplantable Bcr-Abl-positive leukemias was abolished in the absence of Smo expression. Pharmacological Smo inhibition reduced LSCs in vivo and enhanced time to relapse after end of treatment. Our results indicate that Smo inhibition might be an effective treatment strategy to reduce the LSC pool in CML.
引用
收藏
页码:238 / 249
页数:12
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