Expression of late cell cycle genes and an increased proliferative capacity characterize very early relapse of childhood acute lymphoblastic leukemia. |
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Authors: | Renate Kirschner-Schwabe Claudio Lottaz J?rn T?dling Peter Rhein Leonid Karawajew Cornelia Eckert Arend von Stackelberg Ute Ungethüm Dennis Kostka Andreas E Kulozik Wolf-Dieter Ludwig Günter Henze Rainer Spang Christian Hagemeier Karl Seeger |
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Affiliation: | Department of Pediatric Oncology/Hematology, HELIOS Klinikum Berlin, Robert-Roessle-Clinic, Laboratory for Functional Genomics, Charité-Universit?tsmedizin Berlin, Berlin, Germany. |
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Abstract: | PURPOSE: In childhood acute lymphoblastic leukemia (ALL), approximately 25% of patients suffer from relapse. In recurrent disease, despite intensified therapy, overall cure rates of 40% remain unsatisfactory and survival rates are particularly poor in certain subgroups. The probability of long-term survival after relapse is predicted from well-established prognostic factors (i.e., time and site of relapse, immunophenotype, and minimal residual disease). However, the underlying biological determinants of these prognostic factors remain poorly understood. EXPERIMENTAL DESIGN: Aiming at identifying molecular pathways associated with these clinically well-defined prognostic factors, we did gene expression profiling on 60 prospectively collected samples of first relapse patients enrolled on the relapse trial ALL-REZ BFM 2002 of the Berlin-Frankfurt-Münster study group. RESULTS: We show here that patients with very early relapse of ALL are characterized by a distinctive gene expression pattern. We identified a set of 83 genes differentially expressed in very early relapsed ALL compared with late relapsed disease. The vast majority of genes were up-regulated and many were late cell cycle genes with a function in mitosis. In addition, samples from patients with very early relapse showed a significant increase in the percentage of S and G(2)-M phase cells and this correlated well with the expression level of cell cycle genes. CONCLUSIONS: Very early relapse of ALL is characterized by an increased proliferative capacity of leukemic blasts and up-regulated mitotic genes. The latter suggests that novel drugs, targeting late cell cycle proteins, might be beneficial for these patients that typically face a dismal prognosis. |
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