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Molecular Targets for Therapy

Gene expression shift towards normal B cells, decreased proliferative capacity and distinct surface receptors characterize leukemic blasts persisting during induction therapy in childhood acute lymphoblastic leukemia

Leukemia volume 21, pages 897–905 (2007)Cite this article

Abstract

In childhood acute lymphoblastic leukemia (ALL), persistence of leukemic blasts during therapy is of crucial prognostic significance. In the present study, we address molecular and cell biologic features of blasts persisting after 1 week of induction glucocorticoid therapy. Genome-wide gene expression analysis of leukemic samples from precursor B-cell ALL patients (n=18) identified a set of genes differentially expressed in blasts at diagnosis day 0 (d0) and persisting on day 8 (d8). Expression changes indicate a shift towards mature B cells, inhibition of cell cycling and increased expression of adhesion (CD11b/ITGAM) and cytokine (CD119/IFNGR1) receptors. A direct comparison with normal B cells, which are largely therapy resistant, confirmed the differentiation shift at the mRNA (n=10) and protein (n=109) levels. Flow cytometric analysis in independent cohorts of patients confirmed both a decreased proliferative activity (n=13) and the upregulation of CD11b and CD119 (n=29) in d8 blasts. The differentiation shift and low proliferative activity in d8 blasts may account for the persistence of blasts during therapy and affect their sensitivity to further therapeutic treatment. CD11b and CD119 are potential specific markers for d8 blast persistence and detection of minimal residual disease, which warrant further investigation.

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Acknowledgements

We thank Rosemarie Hoffmann, Marianne Dunken and Birgit Oestereich for technical assistance, Dr Ute Ungethüm for performing the Bioanalyzer measurements and Dr Gunnar Cario for helpful discussions. Flow cytometric analysis and quantification of blast cells was a part of a collaborative study within the AIEOP-ALL-BFM MRD Study Group headed by Michael Dworzak (Vienna, Austria), Guiseppe Basso (Padua, Italy), Guiseppe Gaipa (Monza, Italy) and Richard Ratei (Berlin, Germany). This work was also supported by the Federal Ministry for Education and Research (BMBF) in the National Genome Research Network Grant 01GS0443, Wilhelm Sander Stiftung, Grant 2004.072.1 and Gutermuth Stiftung; PR was supported by Deutsche José Carreras Leukämie-Stiftung (Grant DJCLS-F05/09); SS and RS were supported by BMBF Grants 031U109/209 and 01GS0455.

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Authors and Affiliations

  1. Department of Hematology, Oncology, and Tumor Immunology, Robert-Rossle-Clinic at the HELIOS Klinikum Berlin-Buch, Charité Medical School, Berlin, Germany

    P Rhein, R Ratei, W-D Ludwig & L Karawajew

  2. Department of Computational Molecular Biology, Max-Planck-Institute for Molecular Genetics, Berlin, Germany

    S Scheid & R Spang

  3. Department of General Pediatrics, Charité Medical School, Berlin, Germany

    C Hagemeier

  4. Department of Pediatric Oncology/Hematology, Charité Medical School, Berlin, Germany

    K Seeger & R Kirschner-Schwabe

  5. Department of Pediatrics, University Hospital Schleswig-Holstein, Kiel, Germany

    A Moericke & M Schrappe

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Correspondence to L Karawajew.

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

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Rhein, P., Scheid, S., Ratei, R. et al. Gene expression shift towards normal B cells, decreased proliferative capacity and distinct surface receptors characterize leukemic blasts persisting during induction therapy in childhood acute lymphoblastic leukemia. Leukemia 21, 897–905 (2007). https://doi.org/10.1038/sj.leu.2404613

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