{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,16]],"date-time":"2026-10-16T03:50:20Z","timestamp":1792122620743,"version":"4.4.0"},"reference-count":27,"publisher":"American Association for Cancer Research (AACR)","issue":"11","content-domain":{"domain":["aacrjournals.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2016,11,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>A major obstacle to curing chronic myeloid leukemia (CML) is residual disease maintained by tyrosine kinase inhibitor (TKI)\u2013persistent leukemic stem cells (LSC). These are BCR\u2013ABL1 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.<\/jats:p>\n                  <jats:p>Significance: 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\u201357. \u00a92016 AACR.<\/jats:p>\n                  <jats:p>See related article by Xie et al., p. 1237.<\/jats:p>\n                  <jats:p>This article is highlighted in the In This Issue feature, p. 1197<\/jats:p>","DOI":"10.1158\/2159-8290.cd-16-0263","type":"journal-article","created":{"date-parts":[[2016,9,14]],"date-time":"2016-09-14T22:23:50Z","timestamp":1473891830000},"page":"1248-1257","update-policy":"https:\/\/doi.org\/10.1158\/crossmark_policy","source":"Crossref","is-referenced-by-count":129,"title":["Epigenetic Reprogramming Sensitizes CML Stem Cells to Combined EZH2 and Tyrosine Kinase Inhibition"],"prefix":"10.1158","volume":"6","author":[{"given":"Mary T.","family":"Scott","sequence":"first","affiliation":[{"name":"1Epigenetics Unit, Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Glasgow, United Kingdom."},{"name":"2Paul O'Gorman Leukaemia Research Centre, Institute of Cancer Sciences, 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Kingdom."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ross","family":"Kinstrie","sequence":"additional","affiliation":[{"name":"1Epigenetics Unit, Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Glasgow, United Kingdom."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesca","family":"Pellicano","sequence":"additional","affiliation":[{"name":"2Paul O'Gorman Leukaemia Research Centre, Institute of Cancer Sciences, University of Glasgow, Glasgow, United Kingdom."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carla","family":"Guenther","sequence":"additional","affiliation":[{"name":"1Epigenetics Unit, Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Glasgow, United Kingdom."},{"name":"2Paul O'Gorman Leukaemia Research Centre, Institute of Cancer Sciences, University of Glasgow, Glasgow, United 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