title: Selective treatment of mixed-lineage leukemia leukemic stem cells through targeting glycogen synthase kinase 3 and the canonical Wnt/β-catenin pathway.
abstract: OBJECTIVE
  Leukemia carrying mutation of the mixed-lineage leukemia (MLL) gene is particularly refractory to current treatment, and is associated with frequent relapse. We will review the biology of MLL leukemia, and explore the potential of targeting multiple signaling pathways deregulated in MLL leukemic stem cells (LSCs).
  
  
  RESULTS
  Glycogen synthase kinase 3 (GSK3) plays a critical role in mediating Hox/MEIS1 transcriptional program and its inhibition shows promise in suppressing leukemia carrying MLL fusions or aberrant Hox expression. However, recent evidence indicates that GSK3 inhibition can be overcome by hyperactivation of the canonical Wnt signaling pathway in MLL LSCs, whereas suppression of β-catenin resensitizes MLL LSCs to the GSK3 inhibitor treatment. These results suggest a differential GSK3 dependence in different subsets of leukemic populations during disease development.
  
  
  CONCLUSIONS
  On the basis of the results from preclinical model studies, a combination treatment targeting both GSK3 and the canonical Wnt signaling pathway emerges as a promising avenue to eradicate MLL LSCs. Future effort in identifying the key tractable components along these signaling pathways will be critical for the development of effective inhibitors to target this aggressive disease.
authors.affiliation: Leukaemia and Stem Cell Biology Group, Department of Heamatological Medicine, The Rayne Institute, King's College London, London, UK.
authors.forename: Tsz K
authors.initials: TK
authors.lastname: Fung
authors.forename: Arnaud
authors.initials: A
authors.lastname: Gandillet
authors.forename: Chi W E
authors.initials: CW
authors.lastname: So
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000378:metabolism; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors* / Q000502:physiology; D006801:Humans; D015456:Leukemia, Biphenotypic, Acute / Q000378:metabolism* / Q000473:pathology / Q000628:therapy; D058990:Molecular Targeted Therapy; D014411:Neoplastic Stem Cells / Q000378:metabolism* / Q000473:pathology; D051153:Wnt Proteins / Q000378:metabolism*; D060449:Wnt Signaling Pathway / Q000502:physiology*; D051176:beta Catenin / Q000378:metabolism*
chemical_list: D051153:Wnt Proteins; D051176:beta Catenin; D038362:Glycogen Synthase Kinase 3