ATRX loss induces multiple hallmarks of the alternative lengthening of telomeres (ALT) phenotype in human glioma cell lines in a cell line-specific manner

Jacqueline A. Brosnan-Cashman; Ming Yuan; Mindy K. Graham; Anthony J. Rizzo; Kaylar M. Myers; Christine Davis; Rebecca Zhang; David M. Esopi; Eric H. Raabe; Charles G. Eberhart; Christopher M. Heaphy; Alan K. Meeker

doi:10.1371/journal.pone.0204159

ATRX loss induces multiple hallmarks of the alternative lengthening of telomeres (ALT) phenotype in human glioma cell lines in a cell line-specific manner

Jacqueline A. Brosnan-Cashman, Ming Yuan, Mindy K. Graham, Anthony J. Rizzo, Kaylar M. Myers, Christine Davis, Rebecca Zhang, David M. Esopi, Eric H. Raabe, Charles G. Eberhart, Christopher M. Heaphy, Alan K. Meeker^*

^*Corresponding author for this work

Urology

Research output: Contribution to journal › Article › peer-review

44 Scopus citations

Abstract

Cancers must maintain their telomeres at lengths sufficient for cell survival. In several cancer subtypes, a recombination-like mechanism termed alternative lengthening of telomeres (ALT), is frequently used for telomere length maintenance. Cancers utilizing ALT often have lost functional ATRX, a chromatin remodeling protein, through mutation or deletion, thereby strongly implicating ATRX as an ALT suppressor. Herein, we have generated functional ATRX knockouts in four telomerase-positive, ALT-negative human glioma cell lines: MOG-G-UVW, SF188, U-251 and UW479. After loss of ATRX, two of the four cell lines (U-251 and UW479) show multiple characteristics of ALT-positive cells, including ultrabright telomeric DNA foci, ALT-associated PML bodies, and c-circles. However, telomerase activity and overall telomere length heterogeneity are unaffected after ATRX loss, regardless of cellular context. The two cell lines that showed ALT hallmarks after complete ATRX loss also did so upon ATRX depletion via shRNA-mediated knockdown. These results suggest that other genomic or epigenetic events, in addition to ATRX loss, are necessary for the induction of ALT in human cancer.

Original language	English (US)
Article number	e0204159
Journal	PloS one
Volume	13
Issue number	9
DOIs	https://doi.org/10.1371/journal.pone.0204159
State	Published - Sep 2018

Funding

J.B.C was supported by a National Cancer Institute (https://www.cancer.gov) training grant (2T32CA009110-39A1) and a postdoctoral fellowship from the Rally Foundation for Childhood Cancer Research (https://rallyfoundation.org), The Truth 365 (https://www.thetruth365.org), and Open Hands Overflowing Hearts (http:// openhandsoverflowinghearts.org). M.K.G was supported by a National Cancer Institute (https:// www.cancer.gov) training grant (F32CA213742). A. K.M was supported by National Cancer Institute (https://www.cancer.gov) grant 5R01CA172380-05. Core facilities were funded through a National Cancer Institute (https://www.cancer.gov) Cancer Center Support grant (P30 CA006973). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Funding: J.B.C was supported by a National Cancer Institute (https://www.cancer.gov) training grant (2T32CA009 10-39A1) and a postdoctoral fellowship from the Rally Foundation for Childhood Cancer Research (https://rallyfoundation.org), The Truth 365 (https://www.thetruth365.org), and Open Hands Overflowing Hearts (http://openhandsoverflowinghearts.org). M.K.G was supported by a National Cancer Institute (https://www.cancer.gov) training grant (F32CA213742). A.K.M was supported by National Cancer Institute (https://www.cancer.gov) grant 5R01CA172380-05. Core facilities were funded through a National Cancer Institute (https://www.cancer.gov) Cancer Center Support grant (P30 CA006973). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

ASJC Scopus subject areas

General

UN SDGs

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10.1371/journal.pone.0204159

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Brosnan-Cashman, J. A., Yuan, M., Graham, M. K., Rizzo, A. J., Myers, K. M., Davis, C., Zhang, R., Esopi, D. M., Raabe, E. H., Eberhart, C. G., Heaphy, C. M., & Meeker, A. K. (2018). ATRX loss induces multiple hallmarks of the alternative lengthening of telomeres (ALT) phenotype in human glioma cell lines in a cell line-specific manner. PloS one, 13(9), Article e0204159. https://doi.org/10.1371/journal.pone.0204159

@article{28130cb30bea4ec0ac2cb5ca5631f825,

title = "ATRX loss induces multiple hallmarks of the alternative lengthening of telomeres (ALT) phenotype in human glioma cell lines in a cell line-specific manner",

abstract = "Cancers must maintain their telomeres at lengths sufficient for cell survival. In several cancer subtypes, a recombination-like mechanism termed alternative lengthening of telomeres (ALT), is frequently used for telomere length maintenance. Cancers utilizing ALT often have lost functional ATRX, a chromatin remodeling protein, through mutation or deletion, thereby strongly implicating ATRX as an ALT suppressor. Herein, we have generated functional ATRX knockouts in four telomerase-positive, ALT-negative human glioma cell lines: MOG-G-UVW, SF188, U-251 and UW479. After loss of ATRX, two of the four cell lines (U-251 and UW479) show multiple characteristics of ALT-positive cells, including ultrabright telomeric DNA foci, ALT-associated PML bodies, and c-circles. However, telomerase activity and overall telomere length heterogeneity are unaffected after ATRX loss, regardless of cellular context. The two cell lines that showed ALT hallmarks after complete ATRX loss also did so upon ATRX depletion via shRNA-mediated knockdown. These results suggest that other genomic or epigenetic events, in addition to ATRX loss, are necessary for the induction of ALT in human cancer.",

author = "Brosnan-Cashman, {Jacqueline A.} and Ming Yuan and Graham, {Mindy K.} and Rizzo, {Anthony J.} and Myers, {Kaylar M.} and Christine Davis and Rebecca Zhang and Esopi, {David M.} and Raabe, {Eric H.} and Eberhart, {Charles G.} and Heaphy, {Christopher M.} and Meeker, {Alan K.}",

note = "Funding Information: J.B.C was supported by a National Cancer Institute (https://www.cancer.gov) training grant (2T32CA009110-39A1) and a postdoctoral fellowship from the Rally Foundation for Childhood Cancer Research (https://rallyfoundation.org), The Truth 365 (https://www.thetruth365.org), and Open Hands Overflowing Hearts (http:// openhandsoverflowinghearts.org). M.K.G was supported by a National Cancer Institute (https:// www.cancer.gov) training grant (F32CA213742). A. K.M was supported by National Cancer Institute (https://www.cancer.gov) grant 5R01CA172380-05. Core facilities were funded through a National Cancer Institute (https://www.cancer.gov) Cancer Center Support grant (P30 CA006973). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Funding Information: Funding: J.B.C was supported by a National Cancer Institute (https://www.cancer.gov) training grant (2T32CA009 10-39A1) and a postdoctoral fellowship from the Rally Foundation for Childhood Cancer Research (https://rallyfoundation.org), The Truth 365 (https://www.thetruth365.org), and Open Hands Overflowing Hearts (http://openhandsoverflowinghearts.org). M.K.G was supported by a National Cancer Institute (https://www.cancer.gov) training grant (F32CA213742). A.K.M was supported by National Cancer Institute (https://www.cancer.gov) grant 5R01CA172380-05. Core facilities were funded through a National Cancer Institute (https://www.cancer.gov) Cancer Center Support grant (P30 CA006973). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Publisher Copyright: {\textcopyright} 2018 Brosnan-Cashman et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.",

year = "2018",

month = sep,

doi = "10.1371/journal.pone.0204159",

language = "English (US)",

volume = "13",

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Brosnan-Cashman, JA, Yuan, M, Graham, MK, Rizzo, AJ, Myers, KM, Davis, C, Zhang, R, Esopi, DM, Raabe, EH, Eberhart, CG, Heaphy, CM & Meeker, AK 2018, 'ATRX loss induces multiple hallmarks of the alternative lengthening of telomeres (ALT) phenotype in human glioma cell lines in a cell line-specific manner', PloS one, vol. 13, no. 9, e0204159. https://doi.org/10.1371/journal.pone.0204159

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T1 - ATRX loss induces multiple hallmarks of the alternative lengthening of telomeres (ALT) phenotype in human glioma cell lines in a cell line-specific manner

AU - Brosnan-Cashman, Jacqueline A.

AU - Yuan, Ming

AU - Graham, Mindy K.

AU - Rizzo, Anthony J.

AU - Myers, Kaylar M.

AU - Davis, Christine

AU - Zhang, Rebecca

AU - Esopi, David M.

AU - Raabe, Eric H.

AU - Eberhart, Charles G.

AU - Heaphy, Christopher M.

AU - Meeker, Alan K.

N1 - Funding Information: J.B.C was supported by a National Cancer Institute (https://www.cancer.gov) training grant (2T32CA009110-39A1) and a postdoctoral fellowship from the Rally Foundation for Childhood Cancer Research (https://rallyfoundation.org), The Truth 365 (https://www.thetruth365.org), and Open Hands Overflowing Hearts (http:// openhandsoverflowinghearts.org). M.K.G was supported by a National Cancer Institute (https:// www.cancer.gov) training grant (F32CA213742). A. K.M was supported by National Cancer Institute (https://www.cancer.gov) grant 5R01CA172380-05. Core facilities were funded through a National Cancer Institute (https://www.cancer.gov) Cancer Center Support grant (P30 CA006973). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Funding Information: Funding: J.B.C was supported by a National Cancer Institute (https://www.cancer.gov) training grant (2T32CA009 10-39A1) and a postdoctoral fellowship from the Rally Foundation for Childhood Cancer Research (https://rallyfoundation.org), The Truth 365 (https://www.thetruth365.org), and Open Hands Overflowing Hearts (http://openhandsoverflowinghearts.org). M.K.G was supported by a National Cancer Institute (https://www.cancer.gov) training grant (F32CA213742). A.K.M was supported by National Cancer Institute (https://www.cancer.gov) grant 5R01CA172380-05. Core facilities were funded through a National Cancer Institute (https://www.cancer.gov) Cancer Center Support grant (P30 CA006973). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Publisher Copyright: © 2018 Brosnan-Cashman et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

PY - 2018/9

Y1 - 2018/9

N2 - Cancers must maintain their telomeres at lengths sufficient for cell survival. In several cancer subtypes, a recombination-like mechanism termed alternative lengthening of telomeres (ALT), is frequently used for telomere length maintenance. Cancers utilizing ALT often have lost functional ATRX, a chromatin remodeling protein, through mutation or deletion, thereby strongly implicating ATRX as an ALT suppressor. Herein, we have generated functional ATRX knockouts in four telomerase-positive, ALT-negative human glioma cell lines: MOG-G-UVW, SF188, U-251 and UW479. After loss of ATRX, two of the four cell lines (U-251 and UW479) show multiple characteristics of ALT-positive cells, including ultrabright telomeric DNA foci, ALT-associated PML bodies, and c-circles. However, telomerase activity and overall telomere length heterogeneity are unaffected after ATRX loss, regardless of cellular context. The two cell lines that showed ALT hallmarks after complete ATRX loss also did so upon ATRX depletion via shRNA-mediated knockdown. These results suggest that other genomic or epigenetic events, in addition to ATRX loss, are necessary for the induction of ALT in human cancer.

AB - Cancers must maintain their telomeres at lengths sufficient for cell survival. In several cancer subtypes, a recombination-like mechanism termed alternative lengthening of telomeres (ALT), is frequently used for telomere length maintenance. Cancers utilizing ALT often have lost functional ATRX, a chromatin remodeling protein, through mutation or deletion, thereby strongly implicating ATRX as an ALT suppressor. Herein, we have generated functional ATRX knockouts in four telomerase-positive, ALT-negative human glioma cell lines: MOG-G-UVW, SF188, U-251 and UW479. After loss of ATRX, two of the four cell lines (U-251 and UW479) show multiple characteristics of ALT-positive cells, including ultrabright telomeric DNA foci, ALT-associated PML bodies, and c-circles. However, telomerase activity and overall telomere length heterogeneity are unaffected after ATRX loss, regardless of cellular context. The two cell lines that showed ALT hallmarks after complete ATRX loss also did so upon ATRX depletion via shRNA-mediated knockdown. These results suggest that other genomic or epigenetic events, in addition to ATRX loss, are necessary for the induction of ALT in human cancer.

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ATRX loss induces multiple hallmarks of the alternative lengthening of telomeres (ALT) phenotype in human glioma cell lines in a cell line-specific manner

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