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

Cancer Cell. 2008 Sep 9;14(3):238-49. doi: 10.1016/j.ccr.2008.08.003.

Abstract

Resistance 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.

MeSH terms

  • Animals
  • Apoptosis / drug effects
  • Bone Marrow Cells / drug effects
  • Bone Marrow Cells / metabolism
  • Bone Marrow Cells / pathology
  • Bone Marrow Transplantation
  • Cell Proliferation*
  • Drug Therapy, Combination
  • Fetal Stem Cells / cytology
  • Fetal Stem Cells / metabolism
  • Fetal Stem Cells / transplantation
  • Fusion Proteins, bcr-abl / genetics
  • Fusion Proteins, bcr-abl / metabolism*
  • Gene Expression / drug effects
  • Hedgehog Proteins / physiology*
  • Hematopoiesis / drug effects
  • Hematopoiesis / physiology
  • Humans
  • Kruppel-Like Transcription Factors / genetics
  • Kruppel-Like Transcription Factors / metabolism
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive / drug therapy
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive / metabolism
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive / pathology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mice, Transgenic
  • Neoplastic Stem Cells / drug effects
  • Neoplastic Stem Cells / metabolism
  • Neoplastic Stem Cells / pathology*
  • Patched Receptors
  • Pyrimidines / pharmacology
  • Pyrimidines / therapeutic use
  • Receptors, Cell Surface / genetics
  • Receptors, Cell Surface / metabolism
  • Receptors, G-Protein-Coupled / genetics
  • Receptors, G-Protein-Coupled / metabolism
  • Signal Transduction / drug effects
  • Signal Transduction / physiology*
  • Smoothened Receptor
  • Survival Analysis
  • Veratrum Alkaloids / pharmacology
  • Veratrum Alkaloids / therapeutic use
  • Zinc Finger Protein GLI1

Substances

  • 4-methyl-N-(3-(4-methylimidazol-1-yl)-5-(trifluoromethyl)phenyl)-3-((4-pyridin-3-ylpyrimidin-2-yl)amino)benzamide
  • Gli1 protein, mouse
  • Hedgehog Proteins
  • Kruppel-Like Transcription Factors
  • Patched Receptors
  • Pyrimidines
  • Receptors, Cell Surface
  • Receptors, G-Protein-Coupled
  • Smo protein, mouse
  • Smoothened Receptor
  • Veratrum Alkaloids
  • Zinc Finger Protein GLI1
  • Fusion Proteins, bcr-abl
  • cyclopamine