Polycomb genes are associated with response to imatinib in chronic myeloid leukemia.
OBJECTIVE
Imatinib is a tyrosine kinase inhibitor that has revolutionized the treatment of chronic myeloid leukemia (CML). Despite its efficacy, about a third of patients discontinue the treatment due to therapy failure or intolerance. The rational identification of patients less likely to respond to imatinib would be of paramount clinical relevance. We have shown that transmembrane transporter hOCT1 genotyping predicts imatinib activity. In parallel, Polycomb group genes (PcGs) are epigenetic repressors implicated in CML progression and in therapy resistance.


METHODS
We measured the expression of eight PcGs in paired pre- and post-imatinib bone marrow samples from 30 CML patients.


RESULTS
BMI1, PHC3, CBX6 and CBX7 expression was significantly increased during imatinib treatment. Post-treatment levels of CBX6 and CBX7 predicted 3-month response rate. Measurement of post-treatment BMI1 levels improved the predictive power of hOCT1 genotyping.


CONCLUSIONS
These results suggest that the expression levels of PcGs might be useful for a more accurate risk stratification of CML patients.
Experimental Therapeutics, BCCA Research Centre, 675 W 10th Avenue, Vancouver, BC, V5Z 1L3, Canada.|Vancouver Prostate Centre, Vancouver General Hospital, 2660 Oak Street, Vancouver, BC, V6H 3Z6, Canada.|Department of Life Health & Chemical Sciences, The Open University, UK.
Francesco
F
Crea
Department of Clinical & Experimental Medicine, Section of Pharmacology, University of Pisa, Pisa, Italy.
Antonello
A
Di Paolo
Experimental Therapeutics, BCCA Research Centre, 675 W 10th Avenue, Vancouver, BC, V5Z 1L3, Canada.
Hui Hsuan
HH
Liu
Department of Clinical & Experimental Medicine, Section of Pharmacology, University of Pisa, Pisa, Italy.
Marialuisa
M
Polillo
Experimental Therapeutics, BCCA Research Centre, 675 W 10th Avenue, Vancouver, BC, V5Z 1L3, Canada.
Pier-Luc
PL
Clermont
Department of Clinical & Experimental Medicine, Section of Hematology, University of Pisa, Pisa, Italy.
Francesca
F
Guerrini
Department of Clinical & Experimental Medicine, Section of Hematology, University of Pisa, Pisa, Italy.
Elena
E
Ciabatti
Department of Clinical & Experimental Medicine, Section of Hematology, University of Pisa, Pisa, Italy.
Federica
F
Ricci
Department of Clinical & Experimental Medicine, Section of Hematology, University of Pisa, Pisa, Italy.
Claudia
C
Baratè
Department of Clinical & Experimental Medicine, Section of Hematology, University of Pisa, Pisa, Italy.
Giulia
G
Fontanelli
Department of Clinical & Experimental Medicine, Section of Hematology, University of Pisa, Pisa, Italy.
Sara
S
Barsotti
Department of Clinical & Experimental Medicine, Section of Statistics, University of Pisa, Pisa, Italy.
Riccardo
R
Morganti
Department of Clinical & Experimental Medicine, Section of Pharmacology, University of Pisa, Pisa, Italy.
Romano
R
Danesi
Experimental Therapeutics, BCCA Research Centre, 675 W 10th Avenue, Vancouver, BC, V5Z 1L3, Canada.|Vancouver Prostate Centre, Vancouver General Hospital, 2660 Oak Street, Vancouver, BC, V6H 3Z6, Canada.
Yuzhuo
Y
Wang
Department of Clinical & Experimental Medicine, Section of Hematology, University of Pisa, Pisa, Italy.
Mario
M
Petrini
Department of Clinical & Experimental Medicine, Section of Hematology, University of Pisa, Pisa, Italy.
Sara
S
Galimberti
Experimental Therapeutics, BCCA Research Centre, 675 W 10th Avenue, Vancouver, BC, V5Z 1L3, Canada.
Cheryl D
CD
Helgason
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D005260:Female; D015973:Gene Expression Regulation, Leukemic / Q000187:drug effects*; D006801:Humans; D000068877:Imatinib Mesylate / Q000627:therapeutic use*; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy* / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D008957:Models, Genetic; D063150:Polycomb Repressive Complex 1 / Q000235:genetics; D063146:Polycomb-Group Proteins / Q000235:genetics*; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016019:Survival Analysis; D013997:Time Factors; D016896:Treatment Outcome
C069077:BMI1 protein, human; C503627:CBX7 protein, human; C519295:PHC3 protein, human; D063146:Polycomb-Group Proteins; D047428:Protein Kinase Inhibitors; C000609719:cbx6 protein, human; D000068877:Imatinib Mesylate; D063150:Polycomb Repressive Complex 1
BMI1; CBX6; CBX7; Polycomb; imatinib; pharmacoepigenetics