The mTORC1 inhibitor everolimus prevents and treats Eμ-Myc lymphoma by restoring oncogene-induced senescence

Meaghan Wall; Gretchen Poortinga; Kym L. Stanley; Ralph K. Lindemann; Michael Bots; Christopher J. Chan; Megan J. Bywater; Kathryn M. Kinross; Megan V. Astle; Kelly Waldeck; Katherine M. Hannan; Jake Shortt; Mark J. Smyth; Scott W. Lowe; Ross D. Hannan; Richard B. Pearson; Ricky W. Johnstone; Grant A. McArthur

doi:10.1158/2159-8290.CD-12-0404

The mTORC1 inhibitor everolimus prevents and treats Eμ-Myc lymphoma by restoring oncogene-induced senescence

Meaghan Wall, Gretchen Poortinga, Kym L. Stanley, Ralph K. Lindemann, Michael Bots, Christopher J. Chan, Megan J. Bywater, Kathryn M. Kinross, Megan V. Astle, Kelly Waldeck, Katherine M. Hannan, Jake Shortt, Mark J. Smyth, Scott W. Lowe, Ross D. Hannan, Richard B. Pearson, Ricky W. Johnstone, Grant A. McArthur

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Abstract

MYC deregulation is common in human cancer. IG-MYC translocations that are modeled in EμMyc mice occur in almost all cases of Burkitt lymphoma as well as in other B-cell lymphoproliferative disorders. Deregulated expression of MYC results in increased mTOR complex 1 (mTORC1) signaling. As tumors with mTORC1 activation are sensitive to mTORC1 inhibition, we used everolimus, a potent and specific mTORC1 inhibitor, to test the requirement for mTORC1 in the initiation and maintenance of EμMyc lymphoma. Everolimus selectively cleared premalignant B cells from the bone marrow and spleen, restored a normal pattern of B-cell differentiation, and strongly protected against lymphoma development. Established EμMyc lymphoma also regressed after everolimus therapy. Therapeutic response correlated with a cellular senescence phenotype and induction of p53 activity. Therefore, mTORC1-dependent evasion of senescence is critical for cellular transformation and tumor maintenance by MYC in B lymphocytes.

Original language	English
Pages (from-to)	82-95
Number of pages	14
Journal	Cancer Discovery
Volume	3
Issue number	1
DOIs	https://doi.org/10.1158/2159-8290.CD-12-0404
Publication status	Published - Jan 2013
Externally published	Yes

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Wall, M., Poortinga, G., Stanley, K. L., Lindemann, R. K., Bots, M., Chan, C. J., Bywater, M. J., Kinross, K. M., Astle, M. V., Waldeck, K., Hannan, K. M., Shortt, J., Smyth, M. J., Lowe, S. W., Hannan, R. D., Pearson, R. B., Johnstone, R. W., & McArthur, G. A. (2013). The mTORC1 inhibitor everolimus prevents and treats Eμ-Myc lymphoma by restoring oncogene-induced senescence. Cancer Discovery, 3(1), 82-95. https://doi.org/10.1158/2159-8290.CD-12-0404

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title = "The mTORC1 inhibitor everolimus prevents and treats Eμ-Myc lymphoma by restoring oncogene-induced senescence",

abstract = "MYC deregulation is common in human cancer. IG-MYC translocations that are modeled in EμMyc mice occur in almost all cases of Burkitt lymphoma as well as in other B-cell lymphoproliferative disorders. Deregulated expression of MYC results in increased mTOR complex 1 (mTORC1) signaling. As tumors with mTORC1 activation are sensitive to mTORC1 inhibition, we used everolimus, a potent and specific mTORC1 inhibitor, to test the requirement for mTORC1 in the initiation and maintenance of EμMyc lymphoma. Everolimus selectively cleared premalignant B cells from the bone marrow and spleen, restored a normal pattern of B-cell differentiation, and strongly protected against lymphoma development. Established EμMyc lymphoma also regressed after everolimus therapy. Therapeutic response correlated with a cellular senescence phenotype and induction of p53 activity. Therefore, mTORC1-dependent evasion of senescence is critical for cellular transformation and tumor maintenance by MYC in B lymphocytes.",

author = "Meaghan Wall and Gretchen Poortinga and Stanley, {Kym L.} and Lindemann, {Ralph K.} and Michael Bots and Chan, {Christopher J.} and Bywater, {Megan J.} and Kinross, {Kathryn M.} and Astle, {Megan V.} and Kelly Waldeck and Hannan, {Katherine M.} and Jake Shortt and Smyth, {Mark J.} and Lowe, {Scott W.} and Hannan, {Ross D.} and Pearson, {Richard B.} and Johnstone, {Ricky W.} and McArthur, {Grant A.}",

year = "2013",

month = jan,

doi = "10.1158/2159-8290.CD-12-0404",

language = "English",

volume = "3",

pages = "82--95",

journal = "Cancer Discovery",

issn = "2159-8274",

publisher = "American Association for Cancer Research Inc.",

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Wall, M, Poortinga, G, Stanley, KL, Lindemann, RK, Bots, M, Chan, CJ, Bywater, MJ, Kinross, KM, Astle, MV, Waldeck, K, Hannan, KM, Shortt, J, Smyth, MJ, Lowe, SW, Hannan, RD, Pearson, RB, Johnstone, RW & McArthur, GA 2013, 'The mTORC1 inhibitor everolimus prevents and treats Eμ-Myc lymphoma by restoring oncogene-induced senescence', Cancer Discovery, vol. 3, no. 1, pp. 82-95. https://doi.org/10.1158/2159-8290.CD-12-0404

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T1 - The mTORC1 inhibitor everolimus prevents and treats Eμ-Myc lymphoma by restoring oncogene-induced senescence

AU - Wall, Meaghan

AU - Poortinga, Gretchen

AU - Stanley, Kym L.

AU - Lindemann, Ralph K.

AU - Bots, Michael

AU - Chan, Christopher J.

AU - Bywater, Megan J.

AU - Kinross, Kathryn M.

AU - Astle, Megan V.

AU - Waldeck, Kelly

AU - Hannan, Katherine M.

AU - Shortt, Jake

AU - Smyth, Mark J.

AU - Lowe, Scott W.

AU - Hannan, Ross D.

AU - Pearson, Richard B.

AU - Johnstone, Ricky W.

AU - McArthur, Grant A.

PY - 2013/1

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N2 - MYC deregulation is common in human cancer. IG-MYC translocations that are modeled in EμMyc mice occur in almost all cases of Burkitt lymphoma as well as in other B-cell lymphoproliferative disorders. Deregulated expression of MYC results in increased mTOR complex 1 (mTORC1) signaling. As tumors with mTORC1 activation are sensitive to mTORC1 inhibition, we used everolimus, a potent and specific mTORC1 inhibitor, to test the requirement for mTORC1 in the initiation and maintenance of EμMyc lymphoma. Everolimus selectively cleared premalignant B cells from the bone marrow and spleen, restored a normal pattern of B-cell differentiation, and strongly protected against lymphoma development. Established EμMyc lymphoma also regressed after everolimus therapy. Therapeutic response correlated with a cellular senescence phenotype and induction of p53 activity. Therefore, mTORC1-dependent evasion of senescence is critical for cellular transformation and tumor maintenance by MYC in B lymphocytes.

AB - MYC deregulation is common in human cancer. IG-MYC translocations that are modeled in EμMyc mice occur in almost all cases of Burkitt lymphoma as well as in other B-cell lymphoproliferative disorders. Deregulated expression of MYC results in increased mTOR complex 1 (mTORC1) signaling. As tumors with mTORC1 activation are sensitive to mTORC1 inhibition, we used everolimus, a potent and specific mTORC1 inhibitor, to test the requirement for mTORC1 in the initiation and maintenance of EμMyc lymphoma. Everolimus selectively cleared premalignant B cells from the bone marrow and spleen, restored a normal pattern of B-cell differentiation, and strongly protected against lymphoma development. Established EμMyc lymphoma also regressed after everolimus therapy. Therapeutic response correlated with a cellular senescence phenotype and induction of p53 activity. Therefore, mTORC1-dependent evasion of senescence is critical for cellular transformation and tumor maintenance by MYC in B lymphocytes.

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SP - 82

EP - 95

JO - Cancer Discovery

JF - Cancer Discovery

IS - 1

ER -

The mTORC1 inhibitor everolimus prevents and treats Eμ-Myc lymphoma by restoring oncogene-induced senescence

Abstract

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