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Jak-STAT Inhibition Mediates Romidepsin and Mechlorethamine Synergism in Cutaneous T-Cell Lymphoma

  • Author Footnotes
    5 The authors contributed equally to this work.
    Jose R. Cortes
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    5 The authors contributed equally to this work.
    Affiliations
    Institute for Cancer Genetics, Columbia University Irving Medical Center, New York, New York, USA
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  • Author Footnotes
    5 The authors contributed equally to this work.
    Christina C. Patrone
    Footnotes
    5 The authors contributed equally to this work.
    Affiliations
    Department of Dermatology, Columbia University Irving Medical Center, New York, New York, USA
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  • Author Footnotes
    5 The authors contributed equally to this work.
    Stuart Aidan Quinn
    Footnotes
    5 The authors contributed equally to this work.
    Affiliations
    Institute for Cancer Genetics, Columbia University Irving Medical Center, New York, New York, USA
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  • Yuhan Gu
    Affiliations
    Department of Dermatology, Columbia University Irving Medical Center, New York, New York, USA
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  • Marta Sanchez-Martin
    Affiliations
    Institute for Cancer Genetics, Columbia University Irving Medical Center, New York, New York, USA
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  • Adam Mackey
    Affiliations
    Institute for Cancer Genetics, Columbia University Irving Medical Center, New York, New York, USA
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  • Anisha J. Cooke
    Affiliations
    Institute for Cancer Genetics, Columbia University Irving Medical Center, New York, New York, USA
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  • Bobby B. Shih
    Affiliations
    Institute for Cancer Genetics, Columbia University Irving Medical Center, New York, New York, USA
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  • Anouchka P. Laurent
    Affiliations
    Institute for Cancer Genetics, Columbia University Irving Medical Center, New York, New York, USA
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  • Megan H. Trager
    Affiliations
    Department of Dermatology, Columbia University Irving Medical Center, New York, New York, USA
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  • Adolfo A. Ferrando
    Affiliations
    Institute for Cancer Genetics, Columbia University Irving Medical Center, New York, New York, USA

    Department of Pathology and Cell Biology, Columbia University Irving Medical Center, New York, New York, USA

    Department of Pediatrics, Columbia University Irving Medical Center, New York, New York, USA
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  • Author Footnotes
    6 These authors contributed equally as senior authors.
    Larisa J. Geskin
    Footnotes
    6 These authors contributed equally as senior authors.
    Affiliations
    Department of Dermatology, Columbia University Irving Medical Center, New York, New York, USA
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  • Author Footnotes
    6 These authors contributed equally as senior authors.
    Teresa Palomero
    Correspondence
    Correspondence: Teresa Palomero, Institute for Cancer Genetics, Columbia University Irving Medical Center, 1130 Saint Nicholas Avenue, Room 404, New York, New York 10032, USA.
    Footnotes
    6 These authors contributed equally as senior authors.
    Affiliations
    Institute for Cancer Genetics, Columbia University Irving Medical Center, New York, New York, USA

    Department of Pathology and Cell Biology, Columbia University Irving Medical Center, New York, New York, USA
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  • Author Footnotes
    5 The authors contributed equally to this work.
    6 These authors contributed equally as senior authors.
      Sézary syndrome is an aggressive and disseminated form of cutaneous T-cell lymphoma associated with dismal prognosis in which the histone deacetylase inhibitor romidepsin has shown remarkable activity as a single agent. However, clinical responses to romidepsin are typically transient, highlighting the need for more effective therapies. In this study, we show synergistic antilymphoma effects of romidepsin in combination with mechlorethamine, an alkylating agent, in cutaneous T-cell lymphoma cell lines and primary samples with strong antitumor effects in an in vivo model of Sézary syndrome. Mechanistically, gene expression profiling points to abrogation of Jak/signal transducer and activator of transcription (STAT) signaling as an important mediator of this interaction. Consistently, the combination of mechlorethamine plus romidepsin resulted in downregulation of STAT5 phosphorylation in romidepsin-sensitive cell lines and primary Sézary syndrome samples, but not in romidepsin-resistant tumors. Moreover, in further support of Jak/STAT signaling as a modulator of romidepsin activity in cutaneous T-cell lymphoma, treatment with romidepsin in combination with Jak inhibitors resulted in markedly increased therapeutic responses. Overall, these results support a role for romidepsin plus mechlorethamine in combination in the treatment of cutaneous T-cell lymphoma and uncover a previously unrecognized role for Jak/STAT signaling in the response to romidepsin and romidepsin-based combination therapies in Sézary syndrome.

      Abbreviations:

      CTCL (cutaneous T-cell lymphoma), HDAC (histone deacetylase), HDACi (histone deacetylase inhibitor), RNA-seq (RNA-sequencing), SS (Sézary syndrome), STAT (signal transducer and activator of transcription)
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