Expansion of Bcr-Abl-positive leukemic stem cells is dependent on Hedgehog pathway activation.
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.
Dierks
Christine
C
Department of Hematology/Oncology, University of Freiburg, Hugstetter Strasse 55, 79106 Freiburg, Germany. christine.dierks@uniklinik-freiburg.de
Beigi
Ronak
R
Guo
Gui-Rong
GR
Zirlik
Katja
K
Stegert
Mario R
MR
Manley
Paul
P
Trussell
Christopher
C
Schmitt-Graeff
Annette
A
Landwerlin
Klemens
K
Veelken
Hendrik
H
Warmuth
Markus
M
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001854:Bone Marrow Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D016026:Bone Marrow Transplantation; D049109:Cell Proliferation; D004359:Drug Therapy, Combination; D053686:Fetal Stem Cells / Q000166:cytology / Q000378:metabolism / Q000637:transplantation; D016044:Fusion Proteins, bcr-abl / Q000235:genetics / Q000378:metabolism*; D015870:Gene Expression / Q000187:drug effects; D053823:Hedgehog Proteins / Q000502:physiology*; D006410:Hematopoiesis / Q000187:drug effects / Q000502:physiology; D006801:Humans; D051741:Kruppel-Like Transcription Factors / Q000235:genetics / Q000378:metabolism; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D000072079:Patched Receptors; D011743:Pyrimidines / Q000494:pharmacology / Q000627:therapeutic use; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D000072086:Smoothened Receptor; D016019:Survival Analysis; D014704:Veratrum Alkaloids / Q000494:pharmacology / Q000627:therapeutic use; D000071676:Zinc Finger Protein GLI1
C498520:Gli1 protein, mouse; D053823:Hedgehog Proteins; D051741:Kruppel-Like Transcription Factors; D000072079:Patched Receptors; D011743:Pyrimidines; D011956:Receptors, Cell Surface; D043562:Receptors, G-Protein-Coupled; C491022:Smo protein, mouse; D000072086:Smoothened Receptor; D014704:Veratrum Alkaloids; D000071676:Zinc Finger Protein GLI1; D016044:Fusion Proteins, bcr-abl; C498826:nilotinib; C000541:cyclopamine