title: Epigenetic Reprogramming Sensitizes CML Stem Cells to Combined EZH2 and Tyrosine Kinase Inhibition.
abstract: A major obstacle to curing chronic myeloid leukemia (CML) is residual disease maintained by tyrosine kinase inhibitor (TKI)-persistent leukemic stem cells (LSC). These are BCR-ABL1 kinase independent, refractory to apoptosis, and serve as a reservoir to drive relapse or TKI resistance. We demonstrate that Polycomb Repressive Complex 2 is misregulated in chronic phase CML LSCs. This is associated with extensive reprogramming of H3K27me3 targets in LSCs, thus sensitizing them to apoptosis upon treatment with an EZH2-specific inhibitor (EZH2i). EZH2i does not impair normal hematopoietic stem cell survival. Strikingly, treatment of primary CML cells with either EZH2i or TKI alone caused significant upregulation of H3K27me3 targets, and combined treatment further potentiated these effects and resulted in significant loss of LSCs compared to TKI alone, in vitro, and in long-term bone marrow murine xenografts. Our findings point to a promising epigenetic-based therapeutic strategy to more effectively target LSCs in patients with CML receiving TKIs.
  
  
  
  In CML, TKI-persistent LSCs remain an obstacle to cure, and approaches to eradicate them remain a significant unmet clinical need. We demonstrate that EZH2 and H3K27me3 reprogramming is important for LSC survival, but renders LSCs sensitive to the combined effects of EZH2i and TKI. This represents a novel approach to more effectively target LSCs in patients receiving TKI treatment. Cancer Discov; 6(11); 1248-57. ©2016 AACR.See related article by Xie et al., p. 1237This article is highlighted in the In This Issue feature, p. 1197.
authors.affiliation: Epigenetics Unit, Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Glasgow, United Kingdom.|Paul O'Gorman Leukaemia Research Centre, Institute of Cancer Sciences, University of Glasgow, Glasgow, United Kingdom.
authors.forename: Mary T
authors.initials: MT
authors.lastname: Scott
authors.affiliation: Epigenetics Unit, Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Glasgow, United Kingdom.|Paul O'Gorman Leukaemia Research Centre, Institute of Cancer Sciences, University of Glasgow, Glasgow, United Kingdom.
authors.forename: Koorosh
authors.initials: K
authors.lastname: Korfi
authors.affiliation: Epigenetics Unit, Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Glasgow, United Kingdom.
authors.forename: Peter
authors.initials: P
authors.lastname: Saffrey
authors.affiliation: Paul O'Gorman Leukaemia Research Centre, Institute of Cancer Sciences, University of Glasgow, Glasgow, United Kingdom.
authors.forename: Lisa E M
authors.initials: LE
authors.lastname: Hopcroft
authors.affiliation: Epigenetics Unit, Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Glasgow, United Kingdom.
authors.forename: Ross
authors.initials: R
authors.lastname: Kinstrie
authors.affiliation: Paul O'Gorman Leukaemia Research Centre, Institute of Cancer Sciences, University of Glasgow, Glasgow, United Kingdom.
authors.forename: Francesca
authors.initials: F
authors.lastname: Pellicano
authors.affiliation: Epigenetics Unit, Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Glasgow, United Kingdom.|Paul O'Gorman Leukaemia Research Centre, Institute of Cancer Sciences, University of Glasgow, Glasgow, United Kingdom.
authors.forename: Carla
authors.initials: C
authors.lastname: Guenther
authors.affiliation: Paul O'Gorman Leukaemia Research Centre, Institute of Cancer Sciences, University of Glasgow, Glasgow, United Kingdom.
authors.forename: Paolo
authors.initials: P
authors.lastname: Gallipoli
authors.affiliation: Epigenetics Unit, Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Glasgow, United Kingdom.
authors.forename: Michelle
authors.initials: M
authors.lastname: Cruz
authors.affiliation: Paul O'Gorman Leukaemia Research Centre, Institute of Cancer Sciences, University of Glasgow, Glasgow, United Kingdom.
authors.forename: Karen
authors.initials: K
authors.lastname: Dunn
authors.affiliation: Paul O'Gorman Leukaemia Research Centre, Institute of Cancer Sciences, University of Glasgow, Glasgow, United Kingdom.
authors.forename: Heather G
authors.initials: HG
authors.lastname: Jorgensen
authors.affiliation: Paul O'Gorman Leukaemia Research Centre, Institute of Cancer Sciences, University of Glasgow, Glasgow, United Kingdom.
authors.forename: Jennifer E
authors.initials: JE
authors.lastname: Cassels
authors.affiliation: Paul O'Gorman Leukaemia Research Centre, Institute of Cancer Sciences, University of Glasgow, Glasgow, United Kingdom.
authors.forename: Ashley
authors.initials: A
authors.lastname: Hamilton
authors.affiliation: Epigenetics Unit, Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Glasgow, United Kingdom.
authors.forename: Andrew
authors.initials: A
authors.lastname: Crossan
authors.affiliation: Paul O'Gorman Leukaemia Research Centre, Institute of Cancer Sciences, University of Glasgow, Glasgow, United Kingdom.
authors.forename: Amy
authors.initials: A
authors.lastname: Sinclair
authors.affiliation: Paul O'Gorman Leukaemia Research Centre, Institute of Cancer Sciences, University of Glasgow, Glasgow, United Kingdom. David.Vetrie@glasgow.ac.uk Tessa.Holyoake@glasgow.ac.uk.
authors.forename: Tessa L
authors.initials: TL
authors.lastname: Holyoake
authors.affiliation: Epigenetics Unit, Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Glasgow, United Kingdom. David.Vetrie@glasgow.ac.uk Tessa.Holyoake@glasgow.ac.uk.
authors.forename: David
authors.initials: D
authors.lastname: Vetrie
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D065150:Cellular Reprogramming / Q000235:genetics; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D000071221:Enhancer of Zeste Homolog 2 Protein / Q000037:antagonists & inhibitors / Q000235:genetics*; D044127:Epigenesis, Genetic / Q000187:drug effects; D016044:Fusion Proteins, bcr-abl / Q000235:genetics*; D006412:Hematopoietic Stem Cells / Q000187:drug effects / Q000473:pathology; D006801:Humans; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D051379:Mice; D014411:Neoplastic Stem Cells / Q000378:metabolism / Q000473:pathology; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage*
chemical_list: D047428:Protein Kinase Inhibitors; C498409:EZH2 protein, human; D000071221:Enhancer of Zeste Homolog 2 Protein; D016044:Fusion Proteins, bcr-abl