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Blood, 1 September 2004, Vol. 104, No. 5, pp. 1428-1434.
Prepublished online as a Blood First Edition Paper on May 11, 2004; DOI 10.1182/blood-2003-09-3236.
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NEOPLASIA
Fludarabine treatment of patients with chronic lymphocytic leukemia induces a p53-dependent gene expression response
Andreas Rosenwald,
Eric Y. Chuang,
R. Eric Davis,
Adrian Wiestner,
Ash A. Alizadeh,
Diane C. Arthur,
James B. Mitchell,
Gerald E. Marti,
Daniel H. Fowler,
Wyndham H. Wilson, and
Louis M. Staudt
From the Metabolism Branch, Radiation Biology Branch, and Experimental Immunology and Transplantation Branch, Center for Cancer Research, National Cancer Institute (NCI), National Institutes of Health (NIH), Bethesda, MD; the Laboratory of Pathology, Center for Cancer Research, NCI, NIH, Bethesda, MD; the Division of Gene and Cell Therapy, Food and Drug Administration/Center for Biologics Evaluation and Research (FDA/CBER), NIH, Bethesda, MD; and the Department of Biochemistry, Stanford University School of Medicine, Stanford, CA.
Fludarabine, the current standard treatment for B-cell chronic lymphocytic leukemia (CLL), can induce apoptosis in CLL cells in vitro, and a number of molecular mechanisms contribute to its cytotoxicity. Using gene expression profiling, we investigated the molecular consequences of fludarabine treatment of patients with CLL in vivo. In 7 patients with CLL, a consistent gene expression signature of in vivo fludarabine exposure was identified. Many of the fludarabine signature genes were known p53 target genes and genes involved in DNA repair. In vitro treatment of CLL cells with fludarabine induced the same set of genes as observed in vivo, and many of these genes were also induced by in vitro exposure of CLL cells to ionizing radiation. Using isogenic p53 wild-type and null lymphoblastoid cell lines, we confirmed that many of the fludarabine signature genes were also p53 target genes. Because in vivo treatment with fludarabine induces a p53-dependent gene expression response, fludarabine treatment has the potential to select p53-mutant CLL cells, which are more drug resistant and associated with an aggressive clinical course. These considerations suggest that fludarabine treatment should be given in strict accordance to the current National Cancer Institute (NCI) guidelines that have established criteria of disease activity that warrant treatment.
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