title: Kinase-inhibitor-insensitive cancer stem cells in chronic myeloid leukemia.
abstract: BACKGROUND
  Chronic myeloid leukemia (CML) is a myeloproliferative disorder characterized by the translocation t(9;22), coding for the chimeric protein BCR-ABL. The development of BCR-ABL tyrosine kinase inhibitors (TKIs) has dramatically revolutionized and improved CML therapy. However, TKI-based therapy faces a major challenge: the insensitivity of CML leukemic stem cells (LSCs) to TKIs. In particular, while CML progenitor cells and differentiated cells are oncogene addicted, BCR-ABL tyrosine kinase is dispensable for CML LSC survival and maintenance. Notably, in CML, additional cellular mechanisms promote LSC survival and maintenance, rendering these cells able to survive even in the presence of TKI and to eventually promote relapse.
  
  
  METHODS
  This review will focus on the mechanisms of LSC insensitivity to TKI and on the strategies to obtain synthetic lethality with combination therapies.
  
  
  CONCLUSIONS
  Several pathways have been proposed to promote LSC maintenance and described as ideal targets to induce CML LSC exhaustion in combination with TKI. Ongoing clinical trials designed to target some of these pathways will assess which molecular target is relevant for in vivo human LSC survival in a new 'stem-cell targeting' perspective.
authors.affiliation: University Turin, San Luigi Hospital, Division of Hematology and Internal Medicine, Department of Oncology , Orbassano - Turin , Italy giuseppe.saglio@unito.it.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Morotti
authors.forename: Cristina
authors.initials: C
authors.lastname: Panuzzo
authors.forename: Carmen
authors.initials: C
authors.lastname: Fava
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Saglio
mesh_terms: D000818:Animals; D002986:Clinical Trials as Topic / Q000379:methods; D006801:Humans; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy* / Q000201:enzymology*; D014411:Neoplastic Stem Cells / Q000187:drug effects* / Q000201:enzymology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: D047428:Protein Kinase Inhibitors