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Expression of Late Cell Cycle Genes and an Increased Proliferative Capacity Characterize Very Early Relapse of Childhood Acute Lymphoblastic Leukemia

Authors' Affiliations: ¹ Department of Pediatric Oncology/Hematology, ² HELIOS Klinikum Berlin, Robert-Roessle-Clinic, ³ Laboratory for Functional Genomics, and ⁴ Department of General Pediatrics, Charité-Universitätsmedizin Berlin; ⁵ Max Planck Institute for Molecular Genetics; ⁶ Berlin Center for Genome Based Bioinformatics, Berlin, Germany and ⁷ Department of Pediatric Oncology, Hematology, and Immunology, University of Heidelberg, Heidelberg, Germany

Requests for reprints: Christian Hagemeier, Laboratory for Molecular Biology, Department of General Pediatrics, Charité-Universitätsmedizin Berlin, Campus Mitte, Ziegelstrasse 5-9, 10098 Berlin, Germany. Phone: 49-30-450-566-041; Fax: 49-30-450-566-91; E-mail: Christian.Hagemeier{at}charite.de.

Purpose: In childhood acute lymphoblastic leukemia (ALL), 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 G₂-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.