| First Author | Xie H | Year | 2016 |
| Journal | Cancer Discov | Volume | 6 |
| Issue | 11 | Pages | 1237-1247 |
| PubMed ID | 27630126 | Mgi Jnum | J:236852 |
| Mgi Id | MGI:5810008 | Doi | 10.1158/2159-8290.CD-15-1439 |
| Citation | Xie H, et al. (2016) Chronic Myelogenous Leukemia- Initiating Cells Require Polycomb Group Protein EZH2. Cancer Discov 6(11):1237-1247 |
| abstractText | Tyrosine kinase inhibitors (TKI) have revolutionized chronic myelogenous leukemia (CML) management. Disease eradication, however, is hampered by innate resistance of leukemia-initiating cells (LIC) to TKI-induced killing, which also provides the basis for subsequent emergence of TKI-resistant mutants. We report that EZH2, the catalytic subunit of Polycomb Repressive Complex 2 (PRC2), is overexpressed in CML LICs and required for colony formation and survival and cell-cycle progression of CML cell lines. A critical role for EZH2 is supported by genetic studies in a mouse CML model. Inactivation of Ezh2 in conventional conditional mice and through CRISPR/Cas9-mediated gene editing prevents initiation and maintenance of disease and survival of LICs, irrespective of BCR-ABL1 mutational status, and extends survival. Expression of the EZH2 homolog EZH1 is reduced in EZH2-deficient CML LICs, creating a scenario resembling complete loss of PRC2. EZH2 dependence of CML LICs raises prospects for improved therapy of TKI-resistant CML and/or eradication of disease by addition of EZH2 inhibitors. SIGNIFICANCE: This work defines EZH2 as a selective vulnerability for CML cells and their LICs, regardless of BCR-ABL1 mutational status. Our findings provide an experimental rationale for improving disease eradication through judicious use of EZH2 inhibitors within the context of standard-of-care TKI therapy. Cancer Discov; 6(11); 1237-47. (c)2016 AACR.See related article by Scott et al., p. 1248This article is highlighted in the In This Issue feature, p. 1197. |
