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Fludarabine-induced immunosuppression is associated with inhibition of STAT1 signaling

Nature Medicine volume 5, pages 444–447 (1999)Cite this article

Abstract

Fludarabine is a nucleoside analog used in the treatment of hematologic malignancies1 that can induce severe and prolonged immunosuppression2,3. Although it can be incorporated into the DNA of dividing cells, fludarabine is also a potent inhibitor of cells with a low growth fraction4,5, thus it must have other mechanisms of action. STAT1, which is activated in response to many lymphocyte-activating cytokines including the interferons, is essential for cell-mediated immunity, as the absence of this protein is associated with prominent defects in the ability to control viral infections6,7. Here we show that fludarabine, but not the immunosuppressant cyclosporine A, inhibits the cytokine-induced activation of STAT1 and STAT1-dependent gene transcription in normal resting or activated lymphocytes. Fludarabine caused a specific depletion of STAT1 protein (and mRNA) but not of other STATs. This loss of STAT1 was also seen in cells from patients treated with fludarabine in vivo. Brief exposure to fludarabine led to a sustained loss of STAT1, analogous to the prolonged period of immunosuppression induced by exposure to the drug in vivo. Thus, STAT1 may be a useful target in the development of new immunosuppressive and anti-neoplastic agents.

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Figure 1: Fludarabine leads to a loss of STAT1 activation after cytokine treatment of PBMC.
Figure 2: Fludarabine leads to a selective loss of STAT1 protein and mRNA from lymphoid cells.
Figure 3: Fludarabine-induced inhibition in vitro and in vivo.

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Acknowledgements

Acknowledgments This work was supported by grants from the National Cancer Institute (CA41619 and CA66996) and a gift from M. and M. Rubin in honor of M. Idelson.

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Authors and Affiliations

  1. Department of Adult Oncology, Dana-Farber Cancer Institute, 44 Binney St., Boston, 02115, Massachusetts , USA

    David A. Frank, Sudipta Mahajan & Jerome Ritz

  2. Department of Medicine, Harvard Medical School, Boston, 02115, Massachusetts, USA

    David A. Frank & Jerome Ritz

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  1. David A. Frank
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  2. Sudipta Mahajan
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Correspondence to David A. Frank.

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Frank, D., Mahajan, S. & Ritz, J. Fludarabine-induced immunosuppression is associated with inhibition of STAT1 signaling. Nat Med 5, 444–447 (1999). https://doi.org/10.1038/7445

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