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
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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