Expression of late cell cycle genes and an increased proliferative capacity characterize very early relapse of childhood acute lymphoblastic leukemia

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...

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Published in:Clinical cancer research Vol. 12; no. 15; p. 4553
Main Authors: Kirschner-Schwabe, Renate, Lottaz, Claudio, Tödling, Jörn, Rhein, Peter, Karawajew, Leonid, Eckert, Cornelia, von Stackelberg, Arend, Ungethüm, Ute, Kostka, Dennis, Kulozik, Andreas E, Ludwig, Wolf-Dieter, Henze, Günter, Spang, Rainer, Hagemeier, Christian, Seeger, Karl
Format: Journal Article
Language:English
Published: United States 01.08.2006
Subjects:
Cell Cycle - genetics
Cell Cycle Proteins - biosynthesis
Cell Cycle Proteins - genetics
Cell Division - genetics
Cell Proliferation
Child
G2 Phase - genetics
Gene Expression Profiling
Humans
Oligonucleotide Array Sequence Analysis - methods
Precursor Cell Lymphoblastic Leukemia-Lymphoma - diagnosis
Precursor Cell Lymphoblastic Leukemia-Lymphoma - genetics
Predictive Value of Tests
Prognosis
Prospective Studies
Recurrence
Reverse Transcriptase Polymerase Chain Reaction - methods
Up-Regulation - genetics
ISSN:1078-0432
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Summary: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. 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. 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. 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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ISSN:1078-0432
DOI:10.1158/1078-0432.ccr-06-0235