MECHANISM, CONSEQUENCES AND THERAPEUTIC TARGETING OF ABNORMAL IL-15 SIGNALING IN CUTANEOUS T-CELL LYMPHOMA.
(Abstract release date: 05/19/16)
EHA Library. Mishra A. 06/09/16; 132919; E1370
Dr. Anjali Mishra
Contributions
Contributions
Abstract
Abstract: E1370
Type: Eposter Presentation
Background
Cutaneous T-cell lymphoma (CTCL) is a type of non-Hodgkin’s lymphoma of skin-homing T-cells. It represents about 70-80% of all cutaneous lymphoma with unknown pathogenic mechanisms and no cures. There is good evidence to support a divisive role of interleukin-15 (IL-15) in controlling oncogenic processes in CTCL, since it serves to increase T-cell survival, proliferation, migration and invasion in CTCL cell lines.
Aims
While the malignant CD4+ T-cells from CTCL patients appear to produce and be activated by IL-15, the role of this cytokine in the pathogenesis of CTCL remains unresolved. With the intent of gaining insight into mechanisms of IL-15 overexpression and its role in CTCL pathogenesis, we first confirmed the relevance of IL-15 by showing stage-dependent overexpression in lesional skin and peripheral blood CD4+ T-cells from CTCL patients. We elucidated at least one mechanism by which IL-15 can be overexpressed in vivo, and then investigated the biological and clinical aspects of a spontaneous epidermotropic CTCL that develops in mice that constitutively overexpressing IL-15.
Methods
We explored shared molecular aberrations between the CTCL in IL-15 transgenic mice and human CTCL, which could be replicated in normal human T-cells exposed to IL-15. We also interrogated the IL-15 animal model with the purpose of identifying mechanisms and pathways amenable to selective pharmacological targeting for preclinical validation using isotype specific HDAC inhibitor.
Results
Here we report that CTCL patients show increased IL-15 in a clinical stage-dependent manner. Mechanistically, we show that Zeb1 is a transcriptional repressor of IL-15 in T-cells and that hypermethylation of the Zeb1 binding region within the IL-15 promoter, as seen in CTCL patients, prevents Zeb1 binding and causes increased transcription of IL-15. Using a transgenic mouse model of IL-15, we provide evidence that overexpression of IL-15 induces a spontaneous CTCL that mimics the human neoplasm. Excessive autocrine production of IL-15 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 IL-15 downstream signaling with isotype-specific HDAC inhibitors halts (HDAC1) or significantly delays (HDAC6) the progression of CTCL in vivo and provides pre-clinical evidence supporting a hierarchical model of oncogenic signaling in CTCL.
Conclusion
In summary, we provide in vivo evidence that IL-15 likely can have a causal role in the pathogenesis of at least some cases of CTCL, in part via the epigenetic inhibition of the transcriptional repressor, Zeb1, that in turn leads to overexpression of IL-15 and activation of specific HDACs. IL-15 transgenic CTCL mice provide a novel model for studying the development of CTCL and evaluating potential therapies. Selective inhibition of HDAC1/2 produces a comparable halt in the progression of experimental CTCL as that seen with the pan-HDAC inhibitors, and thus may provide an equally potent yet less toxic alternative in the clinic. Our findings not only demonstrate a critical role for IL-15-mediated inflammation in cutaneous T-cell lymphomagenesis, but also uncover a new oncogenic regulatory loop in CTCL involving IL-15, HDAC1, HDAC6 and miR-21 that show differential sensitivity to isotype-specific HDAC inhibitors.
Session topic: E-poster
Keyword(s): HDAC, IL-15, Lymphoma, Therapy
Type: Eposter Presentation
Background
Cutaneous T-cell lymphoma (CTCL) is a type of non-Hodgkin’s lymphoma of skin-homing T-cells. It represents about 70-80% of all cutaneous lymphoma with unknown pathogenic mechanisms and no cures. There is good evidence to support a divisive role of interleukin-15 (IL-15) in controlling oncogenic processes in CTCL, since it serves to increase T-cell survival, proliferation, migration and invasion in CTCL cell lines.
Aims
While the malignant CD4+ T-cells from CTCL patients appear to produce and be activated by IL-15, the role of this cytokine in the pathogenesis of CTCL remains unresolved. With the intent of gaining insight into mechanisms of IL-15 overexpression and its role in CTCL pathogenesis, we first confirmed the relevance of IL-15 by showing stage-dependent overexpression in lesional skin and peripheral blood CD4+ T-cells from CTCL patients. We elucidated at least one mechanism by which IL-15 can be overexpressed in vivo, and then investigated the biological and clinical aspects of a spontaneous epidermotropic CTCL that develops in mice that constitutively overexpressing IL-15.
Methods
We explored shared molecular aberrations between the CTCL in IL-15 transgenic mice and human CTCL, which could be replicated in normal human T-cells exposed to IL-15. We also interrogated the IL-15 animal model with the purpose of identifying mechanisms and pathways amenable to selective pharmacological targeting for preclinical validation using isotype specific HDAC inhibitor.
Results
Here we report that CTCL patients show increased IL-15 in a clinical stage-dependent manner. Mechanistically, we show that Zeb1 is a transcriptional repressor of IL-15 in T-cells and that hypermethylation of the Zeb1 binding region within the IL-15 promoter, as seen in CTCL patients, prevents Zeb1 binding and causes increased transcription of IL-15. Using a transgenic mouse model of IL-15, we provide evidence that overexpression of IL-15 induces a spontaneous CTCL that mimics the human neoplasm. Excessive autocrine production of IL-15 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 IL-15 downstream signaling with isotype-specific HDAC inhibitors halts (HDAC1) or significantly delays (HDAC6) the progression of CTCL in vivo and provides pre-clinical evidence supporting a hierarchical model of oncogenic signaling in CTCL.
Conclusion
In summary, we provide in vivo evidence that IL-15 likely can have a causal role in the pathogenesis of at least some cases of CTCL, in part via the epigenetic inhibition of the transcriptional repressor, Zeb1, that in turn leads to overexpression of IL-15 and activation of specific HDACs. IL-15 transgenic CTCL mice provide a novel model for studying the development of CTCL and evaluating potential therapies. Selective inhibition of HDAC1/2 produces a comparable halt in the progression of experimental CTCL as that seen with the pan-HDAC inhibitors, and thus may provide an equally potent yet less toxic alternative in the clinic. Our findings not only demonstrate a critical role for IL-15-mediated inflammation in cutaneous T-cell lymphomagenesis, but also uncover a new oncogenic regulatory loop in CTCL involving IL-15, HDAC1, HDAC6 and miR-21 that show differential sensitivity to isotype-specific HDAC inhibitors.
Session topic: E-poster
Keyword(s): HDAC, IL-15, Lymphoma, Therapy
Abstract: E1370
Type: Eposter Presentation
Background
Cutaneous T-cell lymphoma (CTCL) is a type of non-Hodgkin’s lymphoma of skin-homing T-cells. It represents about 70-80% of all cutaneous lymphoma with unknown pathogenic mechanisms and no cures. There is good evidence to support a divisive role of interleukin-15 (IL-15) in controlling oncogenic processes in CTCL, since it serves to increase T-cell survival, proliferation, migration and invasion in CTCL cell lines.
Aims
While the malignant CD4+ T-cells from CTCL patients appear to produce and be activated by IL-15, the role of this cytokine in the pathogenesis of CTCL remains unresolved. With the intent of gaining insight into mechanisms of IL-15 overexpression and its role in CTCL pathogenesis, we first confirmed the relevance of IL-15 by showing stage-dependent overexpression in lesional skin and peripheral blood CD4+ T-cells from CTCL patients. We elucidated at least one mechanism by which IL-15 can be overexpressed in vivo, and then investigated the biological and clinical aspects of a spontaneous epidermotropic CTCL that develops in mice that constitutively overexpressing IL-15.
Methods
We explored shared molecular aberrations between the CTCL in IL-15 transgenic mice and human CTCL, which could be replicated in normal human T-cells exposed to IL-15. We also interrogated the IL-15 animal model with the purpose of identifying mechanisms and pathways amenable to selective pharmacological targeting for preclinical validation using isotype specific HDAC inhibitor.
Results
Here we report that CTCL patients show increased IL-15 in a clinical stage-dependent manner. Mechanistically, we show that Zeb1 is a transcriptional repressor of IL-15 in T-cells and that hypermethylation of the Zeb1 binding region within the IL-15 promoter, as seen in CTCL patients, prevents Zeb1 binding and causes increased transcription of IL-15. Using a transgenic mouse model of IL-15, we provide evidence that overexpression of IL-15 induces a spontaneous CTCL that mimics the human neoplasm. Excessive autocrine production of IL-15 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 IL-15 downstream signaling with isotype-specific HDAC inhibitors halts (HDAC1) or significantly delays (HDAC6) the progression of CTCL in vivo and provides pre-clinical evidence supporting a hierarchical model of oncogenic signaling in CTCL.
Conclusion
In summary, we provide in vivo evidence that IL-15 likely can have a causal role in the pathogenesis of at least some cases of CTCL, in part via the epigenetic inhibition of the transcriptional repressor, Zeb1, that in turn leads to overexpression of IL-15 and activation of specific HDACs. IL-15 transgenic CTCL mice provide a novel model for studying the development of CTCL and evaluating potential therapies. Selective inhibition of HDAC1/2 produces a comparable halt in the progression of experimental CTCL as that seen with the pan-HDAC inhibitors, and thus may provide an equally potent yet less toxic alternative in the clinic. Our findings not only demonstrate a critical role for IL-15-mediated inflammation in cutaneous T-cell lymphomagenesis, but also uncover a new oncogenic regulatory loop in CTCL involving IL-15, HDAC1, HDAC6 and miR-21 that show differential sensitivity to isotype-specific HDAC inhibitors.
Session topic: E-poster
Keyword(s): HDAC, IL-15, Lymphoma, Therapy
Type: Eposter Presentation
Background
Cutaneous T-cell lymphoma (CTCL) is a type of non-Hodgkin’s lymphoma of skin-homing T-cells. It represents about 70-80% of all cutaneous lymphoma with unknown pathogenic mechanisms and no cures. There is good evidence to support a divisive role of interleukin-15 (IL-15) in controlling oncogenic processes in CTCL, since it serves to increase T-cell survival, proliferation, migration and invasion in CTCL cell lines.
Aims
While the malignant CD4+ T-cells from CTCL patients appear to produce and be activated by IL-15, the role of this cytokine in the pathogenesis of CTCL remains unresolved. With the intent of gaining insight into mechanisms of IL-15 overexpression and its role in CTCL pathogenesis, we first confirmed the relevance of IL-15 by showing stage-dependent overexpression in lesional skin and peripheral blood CD4+ T-cells from CTCL patients. We elucidated at least one mechanism by which IL-15 can be overexpressed in vivo, and then investigated the biological and clinical aspects of a spontaneous epidermotropic CTCL that develops in mice that constitutively overexpressing IL-15.
Methods
We explored shared molecular aberrations between the CTCL in IL-15 transgenic mice and human CTCL, which could be replicated in normal human T-cells exposed to IL-15. We also interrogated the IL-15 animal model with the purpose of identifying mechanisms and pathways amenable to selective pharmacological targeting for preclinical validation using isotype specific HDAC inhibitor.
Results
Here we report that CTCL patients show increased IL-15 in a clinical stage-dependent manner. Mechanistically, we show that Zeb1 is a transcriptional repressor of IL-15 in T-cells and that hypermethylation of the Zeb1 binding region within the IL-15 promoter, as seen in CTCL patients, prevents Zeb1 binding and causes increased transcription of IL-15. Using a transgenic mouse model of IL-15, we provide evidence that overexpression of IL-15 induces a spontaneous CTCL that mimics the human neoplasm. Excessive autocrine production of IL-15 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 IL-15 downstream signaling with isotype-specific HDAC inhibitors halts (HDAC1) or significantly delays (HDAC6) the progression of CTCL in vivo and provides pre-clinical evidence supporting a hierarchical model of oncogenic signaling in CTCL.
Conclusion
In summary, we provide in vivo evidence that IL-15 likely can have a causal role in the pathogenesis of at least some cases of CTCL, in part via the epigenetic inhibition of the transcriptional repressor, Zeb1, that in turn leads to overexpression of IL-15 and activation of specific HDACs. IL-15 transgenic CTCL mice provide a novel model for studying the development of CTCL and evaluating potential therapies. Selective inhibition of HDAC1/2 produces a comparable halt in the progression of experimental CTCL as that seen with the pan-HDAC inhibitors, and thus may provide an equally potent yet less toxic alternative in the clinic. Our findings not only demonstrate a critical role for IL-15-mediated inflammation in cutaneous T-cell lymphomagenesis, but also uncover a new oncogenic regulatory loop in CTCL involving IL-15, HDAC1, HDAC6 and miR-21 that show differential sensitivity to isotype-specific HDAC inhibitors.
Session topic: E-poster
Keyword(s): HDAC, IL-15, Lymphoma, Therapy
{{ help_message }}
{{filter}}