Chronic myelogenous leukemia-initiating cells require polycomb group protein EZH2

Huafeng Xie, Cong Peng, Jialiang Huang, Bin E. Li, Woojin Kim, Elenoe C. Smith, Yuko Fujiwara, Jun Qi, Giulia Cheloni, Partha P. Das, Minh Nguyen, Shaoguang Li, James E. Bradner, Stuart H. Orkin

Research output: Contribution to journalArticleResearchpeer-review

27 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)1237-1247
Number of pages11
JournalCancer Discovery
Volume6
Issue number11
DOIs
Publication statusPublished - 1 Nov 2016
Externally publishedYes

Cite this

Xie, H., Peng, C., Huang, J., Li, B. E., Kim, W., Smith, E. C., ... Orkin, S. H. (2016). Chronic myelogenous leukemia-initiating cells require polycomb group protein EZH2. Cancer Discovery, 6(11), 1237-1247. https://doi.org/10.1158/2159-8290.CD-15-1439
Xie, Huafeng ; Peng, Cong ; Huang, Jialiang ; Li, Bin E. ; Kim, Woojin ; Smith, Elenoe C. ; Fujiwara, Yuko ; Qi, Jun ; Cheloni, Giulia ; Das, Partha P. ; Nguyen, Minh ; Li, Shaoguang ; Bradner, James E. ; Orkin, Stuart H. / Chronic myelogenous leukemia-initiating cells require polycomb group protein EZH2. In: Cancer Discovery. 2016 ; Vol. 6, No. 11. pp. 1237-1247.
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title = "Chronic myelogenous leukemia-initiating cells require polycomb group protein EZH2",
abstract = "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.",
author = "Huafeng Xie and Cong Peng and Jialiang Huang and Li, {Bin E.} and Woojin Kim and Smith, {Elenoe C.} and Yuko Fujiwara and Jun Qi and Giulia Cheloni and Das, {Partha P.} and Minh Nguyen and Shaoguang Li and Bradner, {James E.} and Orkin, {Stuart H.}",
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Xie, H, Peng, C, Huang, J, Li, BE, Kim, W, Smith, EC, Fujiwara, Y, Qi, J, Cheloni, G, Das, PP, Nguyen, M, Li, S, Bradner, JE & Orkin, SH 2016, 'Chronic myelogenous leukemia-initiating cells require polycomb group protein EZH2', Cancer Discovery, vol. 6, no. 11, pp. 1237-1247. https://doi.org/10.1158/2159-8290.CD-15-1439

Chronic myelogenous leukemia-initiating cells require polycomb group protein EZH2. / Xie, Huafeng; Peng, Cong; Huang, Jialiang; Li, Bin E.; Kim, Woojin; Smith, Elenoe C.; Fujiwara, Yuko; Qi, Jun; Cheloni, Giulia ; Das, Partha P.; Nguyen, Minh; Li, Shaoguang; Bradner, James E.; Orkin, Stuart H.

In: Cancer Discovery, Vol. 6, No. 11, 01.11.2016, p. 1237-1247.

Research output: Contribution to journalArticleResearchpeer-review

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T1 - Chronic myelogenous leukemia-initiating cells require polycomb group protein EZH2

AU - Xie, Huafeng

AU - Peng, Cong

AU - Huang, Jialiang

AU - Li, Bin E.

AU - Kim, Woojin

AU - Smith, Elenoe C.

AU - Fujiwara, Yuko

AU - Qi, Jun

AU - Cheloni, Giulia

AU - Das, Partha P.

AU - Nguyen, Minh

AU - Li, Shaoguang

AU - Bradner, James E.

AU - Orkin, Stuart H.

PY - 2016/11/1

Y1 - 2016/11/1

N2 - 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.

AB - 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.

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