Aberrant Overexpression of IL-15 Initiates Large Granular Lymphocyte Leukemia through Chromosomal Instability and DNA Hypermethylation

Anjali Mishra; Shujun Liu; Gregory H. Sams; Douglas P. Curphey; Ramasamy Santhanam; Laura J. Rush; Deanna Schaefer; Lauren G. Falkenberg; Laura Sullivan; Laura Jaroncyk; Xiaojuan Yang; Harold Fisk; Lai Chu Wu; Christopher Hickey; Jason C. Chandler; Yue Zhong Wu; Nyla A. Heerema; Kenneth K. Chan; Danilo Perrotti; Jianying Zhang; Pierluigi Porcu; Frederick K. Racke; Ramiro Garzon; Robert J. Lee; Guido Marcucci; Michael A. Caligiuri

doi:10.1016/j.ccr.2012.09.009

Aberrant Overexpression of IL-15 Initiates Large Granular Lymphocyte Leukemia through Chromosomal Instability and DNA Hypermethylation

Anjali Mishra, Shujun Liu, Gregory H. Sams, Douglas P. Curphey, Ramasamy Santhanam, Laura J. Rush, Deanna Schaefer, Lauren G. Falkenberg, Laura Sullivan, Laura Jaroncyk, Xiaojuan Yang, Harold Fisk, Lai Chu Wu, Christopher Hickey, Jason C. Chandler, Yue Zhong Wu, Nyla A. Heerema, Kenneth K. Chan, Danilo Perrotti, Jianying ZhangPierluigi Porcu, Frederick K. Racke, Ramiro Garzon, Robert J. Lee, Guido Marcucci, Michael A. Caligiuri

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Abstract

How inflammation causes cancer is unclear. Interleukin-15 (IL-15) is a pro-inflammatory cytokine elevated in human large granular lymphocyte (LGL) leukemia. Mice overexpressing IL-15 develop LGL leukemia. Here, we show that prolonged in vitro exposure of wild-type (WT) LGL to IL-15 results in Myc-mediated upregulation of aurora kinases, centrosome aberrancies, and aneuploidy. Simultaneously, IL-15 represses miR-29b via induction of Myc/NF-κBp65/Hdac-1, resulting in Dnmt3b overexpression and DNA hypermethylation. All this is validated in human LGL leukemia. Adoptive transfer of WT LGL cultured with IL-15 led to malignant transformation in vivo. Drug targeting that reverses miR-29b repression cures otherwise fatal LGL leukemia. We show how excessive IL-15 initiates cancer and demonstrate effective drug targeting for potential therapy of human LGL leukemia.

Original language	English (US)
Pages (from-to)	645-655
Number of pages	11
Journal	Cancer Cell
Volume	22
Issue number	5
DOIs	https://doi.org/10.1016/j.ccr.2012.09.009
State	Published - Nov 13 2012
Externally published	Yes

Bibliographical note

Funding Information:
This work is supported by National Cancer Institute Grants CA16058, CA95426, CA68458, CA09338 (to M.A.C.); CA140158 (to M.A.C. and G.M.); CA102031 (to G.M.); CA149623 (to S.L.); and NSF EEC-0914790 (to R.J.L.). The authors wish to thank Kathleen McConnell for technical assistance; we thank Mr. and Mrs. Thomas Lauber and Greif, Inc. for their support.

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10.1016/j.ccr.2012.09.009

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Mishra, A., Liu, S., Sams, G. H., Curphey, D. P., Santhanam, R., Rush, L. J., Schaefer, D., Falkenberg, L. G., Sullivan, L., Jaroncyk, L., Yang, X., Fisk, H., Wu, L. C., Hickey, C., Chandler, J. C., Wu, Y. Z., Heerema, N. A., Chan, K. K., Perrotti, D., ... Caligiuri, M. A. (2012). Aberrant Overexpression of IL-15 Initiates Large Granular Lymphocyte Leukemia through Chromosomal Instability and DNA Hypermethylation. Cancer Cell, 22(5), 645-655. https://doi.org/10.1016/j.ccr.2012.09.009

Mishra, A, Liu, S, Sams, GH, Curphey, DP, Santhanam, R, Rush, LJ, Schaefer, D, Falkenberg, LG, Sullivan, L, Jaroncyk, L, Yang, X, Fisk, H, Wu, LC, Hickey, C, Chandler, JC, Wu, YZ, Heerema, NA, Chan, KK, Perrotti, D, Zhang, J, Porcu, P, Racke, FK, Garzon, R, Lee, RJ, Marcucci, G & Caligiuri, MA 2012, 'Aberrant Overexpression of IL-15 Initiates Large Granular Lymphocyte Leukemia through Chromosomal Instability and DNA Hypermethylation', Cancer Cell, vol. 22, no. 5, pp. 645-655. https://doi.org/10.1016/j.ccr.2012.09.009

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title = "Aberrant Overexpression of IL-15 Initiates Large Granular Lymphocyte Leukemia through Chromosomal Instability and DNA Hypermethylation",

abstract = "How inflammation causes cancer is unclear. Interleukin-15 (IL-15) is a pro-inflammatory cytokine elevated in human large granular lymphocyte (LGL) leukemia. Mice overexpressing IL-15 develop LGL leukemia. Here, we show that prolonged in vitro exposure of wild-type (WT) LGL to IL-15 results in Myc-mediated upregulation of aurora kinases, centrosome aberrancies, and aneuploidy. Simultaneously, IL-15 represses miR-29b via induction of Myc/NF-κBp65/Hdac-1, resulting in Dnmt3b overexpression and DNA hypermethylation. All this is validated in human LGL leukemia. Adoptive transfer of WT LGL cultured with IL-15 led to malignant transformation in vivo. Drug targeting that reverses miR-29b repression cures otherwise fatal LGL leukemia. We show how excessive IL-15 initiates cancer and demonstrate effective drug targeting for potential therapy of human LGL leukemia.",

author = "Anjali Mishra and Shujun Liu and Sams, {Gregory H.} and Curphey, {Douglas P.} and Ramasamy Santhanam and Rush, {Laura J.} and Deanna Schaefer and Falkenberg, {Lauren G.} and Laura Sullivan and Laura Jaroncyk and Xiaojuan Yang and Harold Fisk and Wu, {Lai Chu} and Christopher Hickey and Chandler, {Jason C.} and Wu, {Yue Zhong} and Heerema, {Nyla A.} and Chan, {Kenneth K.} and Danilo Perrotti and Jianying Zhang and Pierluigi Porcu and Racke, {Frederick K.} and Ramiro Garzon and Lee, {Robert J.} and Guido Marcucci and Caligiuri, {Michael A.}",

note = "Funding Information: This work is supported by National Cancer Institute Grants CA16058, CA95426, CA68458, CA09338 (to M.A.C.); CA140158 (to M.A.C. and G.M.); CA102031 (to G.M.); CA149623 (to S.L.); and NSF EEC-0914790 (to R.J.L.). The authors wish to thank Kathleen McConnell for technical assistance; we thank Mr. and Mrs. Thomas Lauber and Greif, Inc. for their support. ",

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doi = "10.1016/j.ccr.2012.09.009",

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T1 - Aberrant Overexpression of IL-15 Initiates Large Granular Lymphocyte Leukemia through Chromosomal Instability and DNA Hypermethylation

AU - Mishra, Anjali

AU - Liu, Shujun

AU - Sams, Gregory H.

AU - Curphey, Douglas P.

AU - Santhanam, Ramasamy

AU - Rush, Laura J.

AU - Schaefer, Deanna

AU - Falkenberg, Lauren G.

AU - Sullivan, Laura

AU - Jaroncyk, Laura

AU - Yang, Xiaojuan

AU - Fisk, Harold

AU - Wu, Lai Chu

AU - Hickey, Christopher

AU - Chandler, Jason C.

AU - Wu, Yue Zhong

AU - Heerema, Nyla A.

AU - Chan, Kenneth K.

AU - Perrotti, Danilo

AU - Zhang, Jianying

AU - Porcu, Pierluigi

AU - Racke, Frederick K.

AU - Garzon, Ramiro

AU - Lee, Robert J.

AU - Marcucci, Guido

AU - Caligiuri, Michael A.

N1 - Funding Information: This work is supported by National Cancer Institute Grants CA16058, CA95426, CA68458, CA09338 (to M.A.C.); CA140158 (to M.A.C. and G.M.); CA102031 (to G.M.); CA149623 (to S.L.); and NSF EEC-0914790 (to R.J.L.). The authors wish to thank Kathleen McConnell for technical assistance; we thank Mr. and Mrs. Thomas Lauber and Greif, Inc. for their support.

PY - 2012/11/13

Y1 - 2012/11/13

N2 - How inflammation causes cancer is unclear. Interleukin-15 (IL-15) is a pro-inflammatory cytokine elevated in human large granular lymphocyte (LGL) leukemia. Mice overexpressing IL-15 develop LGL leukemia. Here, we show that prolonged in vitro exposure of wild-type (WT) LGL to IL-15 results in Myc-mediated upregulation of aurora kinases, centrosome aberrancies, and aneuploidy. Simultaneously, IL-15 represses miR-29b via induction of Myc/NF-κBp65/Hdac-1, resulting in Dnmt3b overexpression and DNA hypermethylation. All this is validated in human LGL leukemia. Adoptive transfer of WT LGL cultured with IL-15 led to malignant transformation in vivo. Drug targeting that reverses miR-29b repression cures otherwise fatal LGL leukemia. We show how excessive IL-15 initiates cancer and demonstrate effective drug targeting for potential therapy of human LGL leukemia.

AB - How inflammation causes cancer is unclear. Interleukin-15 (IL-15) is a pro-inflammatory cytokine elevated in human large granular lymphocyte (LGL) leukemia. Mice overexpressing IL-15 develop LGL leukemia. Here, we show that prolonged in vitro exposure of wild-type (WT) LGL to IL-15 results in Myc-mediated upregulation of aurora kinases, centrosome aberrancies, and aneuploidy. Simultaneously, IL-15 represses miR-29b via induction of Myc/NF-κBp65/Hdac-1, resulting in Dnmt3b overexpression and DNA hypermethylation. All this is validated in human LGL leukemia. Adoptive transfer of WT LGL cultured with IL-15 led to malignant transformation in vivo. Drug targeting that reverses miR-29b repression cures otherwise fatal LGL leukemia. We show how excessive IL-15 initiates cancer and demonstrate effective drug targeting for potential therapy of human LGL leukemia.

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SN - 1535-6108

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SP - 645

EP - 655

JO - Cancer Cell

JF - Cancer Cell

IS - 5

ER -

Aberrant Overexpression of IL-15 Initiates Large Granular Lymphocyte Leukemia through Chromosomal Instability and DNA Hypermethylation

Abstract

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