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Genome-wide expression analysis of paired diagnosis–relapse samples in ALL indicates involvement of pathways related to DNA replication, cell cycle and DNA repair, independent of immune phenotype

Leukemia volume 24, pages 491–499 (2010)Cite this article

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Abstract

Almost a quarter of pediatric patients with acute lymphoblastic leukemia (ALL) suffer from relapses. The biological mechanisms underlying therapy response and development of relapses have remained unclear. In an attempt to better understand this phenomenon, we have analyzed 41 matched diagnosis–relapse pairs of ALL patients using genome-wide expression arrays (82 arrays) on purified leukemic cells. In roughly half of the patients, very few differences between diagnosis and relapse samples were found (‘stable group’), suggesting that mostly extra-leukemic factors (for example, drug distribution, drug metabolism, compliance) contributed to the relapse. Therefore, we focused our further analysis on 20 sample pairs with clear differences in gene expression (‘skewed group’), reasoning that these would allow us to better study the biological mechanisms underlying relapsed ALL. After finding the differences between diagnosis and relapse pairs in this group, we identified four major gene clusters corresponding to several pathways associated with changes in cell cycle, DNA replication, recombination and repair, as well as B-cell developmental genes. We also identified cancer genes commonly associated with colon carcinomas and ubiquitination to be upregulated in relapsed ALL. Thus, about half of the relapses are due to the selection or emergence of a clone with deregulated expression of genes involved in pathways that regulate B-cell signaling, development, cell cycle, cellular division and replication.

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Acknowledgements

We thank Patricia Hoogeveen for technical assistance and Dr Ton Langerak for stimulating discussions. We also thank the Dutch Childhood Oncology Group (head: Dr Valerie de Haas) for help in providing samples and patient data.

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Author notes

  1. D de Ridder, T Szczepanski, T Schonewille and E C E van der Linden: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Immunology, Erasmus MC, University Medical Center, Rotterdam, The Netherlands

    F J T Staal, T Szczepanski, T Schonewille, E C E van der Linden, V H J van der Velden & J J M van Dongen

  2. Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, Leiden, The Netherlands

    F J T Staal

  3. Delft Bioinformatics Lab, Faculty of Electrical Engineering, Mathematics and Computer Science, Delft University of Technology, Delft, The Netherlands

    D de Ridder

  4. Department of Pediatric Hematology and Oncology, Medical University of Silesia, Zabrze, Poland

    T Szczepanski

  5. Dutch Childhood Oncology Group (DCOG), The Hague, The Netherlands

    E R van Wering

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  1. F J T Staal
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Correspondence to F J T Staal.

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Supplementary Information accompanies the paper on the Leukemia website (http://www.nature.com/leu)

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Staal, F., de Ridder, D., Szczepanski, T. et al. Genome-wide expression analysis of paired diagnosis–relapse samples in ALL indicates involvement of pathways related to DNA replication, cell cycle and DNA repair, independent of immune phenotype. Leukemia 24, 491–499 (2010). https://doi.org/10.1038/leu.2009.286

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