Mechanism, Consequences, and Therapeutic Targeting of Abnormal IL15 Signaling in Cutaneous T-cell Lymphoma

Anjali Mishra, Krista La Perle, Sonya Kwiatkowski, Laura A Sullivan, Gregory H Sams, Jessica Johns, Douglas P Curphey, Jing Wen, Kathleen McConnell, Jun Qi, Henry Wong, Giandomenico Russo, Jianying Zhang, Guido Marcucci, James E. Bradner, Pierluigi Porcu, Michael A. Caligiuri

Research output: Contribution to journalArticle

Abstract

UNLABELLED: Cutaneous T-cell lymphoma (CTCL) is the most common type of primary cutaneous lymphoma. Here, we report that patients with CTCL show increased IL15 in a clinical stage-dependent manner. Mechanistically, we show that ZEB1 is a transcriptional repressor of IL15 in T cells and that hypermethylation of the ZEB1 binding region within the IL15 promoter, as seen in patients with CTCL, prevents ZEB1 binding and causes increased transcription of IL15 Using a transgenic mouse model of IL15, we provide evidence that overexpression of IL15 induces a spontaneous CTCL that mimics the human neoplasm. Excessive autocrine production of IL15 in T cells inhibits an HDAC1-mediated negative autoregulatory loop, resulting in the upregulation of HDAC1 and HDAC6 and transcriptional induction of the onco-miR-21. Interruption of IL15 downstream signaling with isotype-specific HDAC inhibitors halts (HDAC1) or significantly delays (HDAC6) the progression of CTCL in vivo and provides preclinical evidence supporting a hierarchical model of oncogenic signaling in CTCL.

SIGNIFICANCE: To date, CTCL pathogenesis remains unknown, and there are no curative therapies. Our findings not only demonstrate a critical role for IL15-mediated inflammation in cutaneous T-cell lymphomagenesis, but also uncover a new oncogenic regulatory loop in CTCL involving IL15, HDAC1, HDAC6, and miR-21 that shows differential sensitivity to isotype-specific HDAC inhibitors. Cancer Discov; 6(9); 986-1005. ©2016 AACR.This article is highlighted in the In This Issue feature, p. 932.

Original languageEnglish
Pages (from-to)986-1005
Number of pages20
JournalCancer Discovery
Volume6
Issue number9
DOIs
Publication statusPublished - Sep 2016

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Cutaneous T-Cell Lymphoma
Interleukin-15
Therapeutics
Histone Deacetylase Inhibitors
T-Lymphocytes
Skin
Transgenic Mice
Lymphoma
Neoplasms
Up-Regulation
Inflammation

Keywords

  • Journal Article

Cite this

Mishra, A., La Perle, K., Kwiatkowski, S., Sullivan, L. A., Sams, G. H., Johns, J., ... Caligiuri, M. A. (2016). Mechanism, Consequences, and Therapeutic Targeting of Abnormal IL15 Signaling in Cutaneous T-cell Lymphoma. Cancer Discovery, 6(9), 986-1005. https://doi.org/10.1158/2159-8290.CD-15-1297

Mechanism, Consequences, and Therapeutic Targeting of Abnormal IL15 Signaling in Cutaneous T-cell Lymphoma. / Mishra, Anjali; La Perle, Krista; Kwiatkowski, Sonya; Sullivan, Laura A; Sams, Gregory H; Johns, Jessica; Curphey, Douglas P; Wen, Jing; McConnell, Kathleen; Qi, Jun; Wong, Henry; Russo, Giandomenico; Zhang, Jianying; Marcucci, Guido; Bradner, James E.; Porcu, Pierluigi; Caligiuri, Michael A.

In: Cancer Discovery, Vol. 6, No. 9, 09.2016, p. 986-1005.

Research output: Contribution to journalArticle

Mishra, A, La Perle, K, Kwiatkowski, S, Sullivan, LA, Sams, GH, Johns, J, Curphey, DP, Wen, J, McConnell, K, Qi, J, Wong, H, Russo, G, Zhang, J, Marcucci, G, Bradner, JE, Porcu, P & Caligiuri, MA 2016, 'Mechanism, Consequences, and Therapeutic Targeting of Abnormal IL15 Signaling in Cutaneous T-cell Lymphoma', Cancer Discovery, vol. 6, no. 9, pp. 986-1005. https://doi.org/10.1158/2159-8290.CD-15-1297
Mishra, Anjali ; La Perle, Krista ; Kwiatkowski, Sonya ; Sullivan, Laura A ; Sams, Gregory H ; Johns, Jessica ; Curphey, Douglas P ; Wen, Jing ; McConnell, Kathleen ; Qi, Jun ; Wong, Henry ; Russo, Giandomenico ; Zhang, Jianying ; Marcucci, Guido ; Bradner, James E. ; Porcu, Pierluigi ; Caligiuri, Michael A. / Mechanism, Consequences, and Therapeutic Targeting of Abnormal IL15 Signaling in Cutaneous T-cell Lymphoma. In: Cancer Discovery. 2016 ; Vol. 6, No. 9. pp. 986-1005.
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AU - Sullivan, Laura A

AU - Sams, Gregory H

AU - Johns, Jessica

AU - Curphey, Douglas P

AU - Wen, Jing

AU - McConnell, Kathleen

AU - Qi, Jun

AU - Wong, Henry

AU - Russo, Giandomenico

AU - Zhang, Jianying

AU - Marcucci, Guido

AU - Bradner, James E.

AU - Porcu, Pierluigi

AU - Caligiuri, Michael A.

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N2 - UNLABELLED: Cutaneous T-cell lymphoma (CTCL) is the most common type of primary cutaneous lymphoma. Here, we report that patients with CTCL show increased IL15 in a clinical stage-dependent manner. Mechanistically, we show that ZEB1 is a transcriptional repressor of IL15 in T cells and that hypermethylation of the ZEB1 binding region within the IL15 promoter, as seen in patients with CTCL, prevents ZEB1 binding and causes increased transcription of IL15 Using a transgenic mouse model of IL15, we provide evidence that overexpression of IL15 induces a spontaneous CTCL that mimics the human neoplasm. Excessive autocrine production of IL15 in T cells inhibits an HDAC1-mediated negative autoregulatory loop, resulting in the upregulation of HDAC1 and HDAC6 and transcriptional induction of the onco-miR-21. Interruption of IL15 downstream signaling with isotype-specific HDAC inhibitors halts (HDAC1) or significantly delays (HDAC6) the progression of CTCL in vivo and provides preclinical evidence supporting a hierarchical model of oncogenic signaling in CTCL.SIGNIFICANCE: To date, CTCL pathogenesis remains unknown, and there are no curative therapies. Our findings not only demonstrate a critical role for IL15-mediated inflammation in cutaneous T-cell lymphomagenesis, but also uncover a new oncogenic regulatory loop in CTCL involving IL15, HDAC1, HDAC6, and miR-21 that shows differential sensitivity to isotype-specific HDAC inhibitors. Cancer Discov; 6(9); 986-1005. ©2016 AACR.This article is highlighted in the In This Issue feature, p. 932.

AB - UNLABELLED: Cutaneous T-cell lymphoma (CTCL) is the most common type of primary cutaneous lymphoma. Here, we report that patients with CTCL show increased IL15 in a clinical stage-dependent manner. Mechanistically, we show that ZEB1 is a transcriptional repressor of IL15 in T cells and that hypermethylation of the ZEB1 binding region within the IL15 promoter, as seen in patients with CTCL, prevents ZEB1 binding and causes increased transcription of IL15 Using a transgenic mouse model of IL15, we provide evidence that overexpression of IL15 induces a spontaneous CTCL that mimics the human neoplasm. Excessive autocrine production of IL15 in T cells inhibits an HDAC1-mediated negative autoregulatory loop, resulting in the upregulation of HDAC1 and HDAC6 and transcriptional induction of the onco-miR-21. Interruption of IL15 downstream signaling with isotype-specific HDAC inhibitors halts (HDAC1) or significantly delays (HDAC6) the progression of CTCL in vivo and provides preclinical evidence supporting a hierarchical model of oncogenic signaling in CTCL.SIGNIFICANCE: To date, CTCL pathogenesis remains unknown, and there are no curative therapies. Our findings not only demonstrate a critical role for IL15-mediated inflammation in cutaneous T-cell lymphomagenesis, but also uncover a new oncogenic regulatory loop in CTCL involving IL15, HDAC1, HDAC6, and miR-21 that shows differential sensitivity to isotype-specific HDAC inhibitors. Cancer Discov; 6(9); 986-1005. ©2016 AACR.This article is highlighted in the In This Issue feature, p. 932.

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