Expansion of Bcr-Abl-positive leukemic stem cells is dependent on Hedgehog pathway activation
Autor: | Paul W. Manley, Ronak Beigi, Gui-Rong Guo, Klemens Landwerlin, Christopher Trussell, Markus Warmuth, Mario R. Stegert, Hendrik Veelken, Annette Schmitt-Graeff, Katja Zirlik, Christine Dierks |
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Rok vydání: | 2007 |
Předmět: |
Patched Receptors
Cancer Research Fusion Proteins bcr-abl Kruppel-Like Transcription Factors Gene Expression Apoptosis Bone Marrow Cells Mice Transgenic Receptors Cell Surface CELLCYCLE Biology Zinc Finger Protein GLI1 Receptors G-Protein-Coupled Mice Downregulation and upregulation hemic and lymphatic diseases Leukemia Myelogenous Chronic BCR-ABL Positive medicine Animals Humans Hedgehog Proteins neoplasms Bone Marrow Transplantation Cell Proliferation Mice Knockout Fetal Stem Cells Veratrum Alkaloids Myeloid leukemia Cell Biology Cell cycle medicine.disease STEMCELL Smoothened Receptor Survival Analysis Hedgehog signaling pathway Hematopoiesis Mice Inbred C57BL Leukemia Haematopoiesis Pyrimidines Oncology Immunology Cancer research Neoplastic Stem Cells Drug Therapy Combination Stem cell Signal Transduction |
Zdroj: | Cancer cell. 14(3) |
ISSN: | 1878-3686 |
Popis: | SummaryResistance of Bcr-Abl-positive leukemic stem cells (LSCs) to imatinib treatment in patients with chronic myeloid leukemia (CML) 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. |
Databáze: | OpenAIRE |
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