title: Sonic hedgehog maintains survival and growth of chronic myeloid leukemia progenitor cells through β-catenin signaling.
abstract: Sonic hedgehog (Shh) signaling plays an important role in many human cancers and cancer stem cells. Here we investigate the activity and functional role of Shh signaling in chronic myeloid leukemia (CML) and leukemia progenitor cells. Differential activation of Shh signaling was found in about 50% CML chronic phase samples, about 70% of CML accelerated phase samples, and >80% CML blast crisis phase samples. Deregulated activation of Shh signaling was observed in CD34(+) and c-kit(+) leukemia progenitor cells. Stimulation of Shh signaling with exogenous Shh peptide induced expansion of CD34(+) and c-kit(+) progenitor cells (p < 0.05), inversely, blocking the pathway with signal inhibitor induced cell apoptosis (p < 0.05). Low level of Shh protein was observed in CML bone marrow stromal cells, and CD34(+) progenitor cells are less sensitive to exogenous Shh peptide and more sensitive to cyclopamine than CD34(-) cells (p < 0.05), implying cell-autonomous activation of Shh signaling play a predominant role in progenitor cells. Coactivation of Shh and β-catenin signaling was found in CD34(+) and c-kit(+) progenitor cells. Administration of Shh-neutralizing antibody or Wnt3a-neutralizing antibody in c-kit(+) progenitor cells induced cell apoptosis; however, Wnt3a peptide could salvage cell apoptosis, while Shh peptide failed to revert anti-Wnt3a-induced cell apoptosis. C-MYC, GLI1, BCL-2, and P21 were also found to be downstream targets of Shh signaling, mediating apoptosis or G(2)/M cell cycle arrest of progenitor cells. Our results demonstrate that autoactivated Shh signaling provides survival and proliferative cues in CML progenitor cells through downstream β-catenin signaling, suggesting a novel therapeutic approach in CML.
authors.affiliation: Department of Hematology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
authors.forename: Wenxia
authors.initials: W
authors.lastname: Su
authors.forename: Fankai
authors.initials: F
authors.lastname: Meng
authors.forename: Lifang
authors.initials: L
authors.lastname: Huang
authors.forename: Miao
authors.initials: M
authors.lastname: Zheng
authors.forename: Wenli
authors.initials: W
authors.lastname: Liu
authors.forename: Hanying
authors.initials: H
authors.lastname: Sun
mesh_terms: D000328:Adult; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D002455:Cell Division / Q000187:drug effects / Q000502:physiology; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000502:physiology; D005260:Female; D016195:G2 Phase / Q000187:drug effects; D053823:Hedgehog Proteins / Q000494:pharmacology / Q000502:physiology*; D006412:Hematopoietic Stem Cells / Q000187:drug effects / Q000473:pathology; D006801:Humans; D020014:K562 Cells / Q000187:drug effects; D015465:Leukemia, Myeloid, Accelerated Phase / Q000473:pathology*; D015466:Leukemia, Myeloid, Chronic-Phase / Q000473:pathology*; D008297:Male; D009363:Neoplasm Proteins / Q000502:physiology*; D010446:Peptide Fragments / Q000494:pharmacology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000502:physiology; D016271:Proto-Oncogene Proteins c-myc / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology*; D014157:Transcription Factors / Q000502:physiology; D014704:Veratrum Alkaloids / Q000494:pharmacology; D060509:Wnt3A Protein / Q000037:antagonists & inhibitors / Q000502:physiology; D000071676:Zinc Finger Protein GLI1; D051176:beta Catenin / Q000502:physiology*
chemical_list: C493956:CDKN1A protein, human; C495270:CTNNB1 protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; C400551:GLI1 protein, human; D053823:Hedgehog Proteins; C489427:MYC protein, human; D009363:Neoplasm Proteins; D010446:Peptide Fragments; D019253:Proto-Oncogene Proteins c-bcl-2; D016271:Proto-Oncogene Proteins c-myc; C509239:SHH protein, human; D014157:Transcription Factors; D014704:Veratrum Alkaloids; C555510:WNT3A protein, human; D060509:Wnt3A Protein; D000071676:Zinc Finger Protein GLI1; D051176:beta Catenin; C000541:cyclopamine