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PAX5 overexpression is not enough to reestablish the mature B-cell phenotype in classical Hodgkin lymphoma

Leukemia volume 28, pages 213–216 (2014)Cite this article

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The transcription factor PAX5, consistently expressed from the pro-B to the mature B-cell stage, plays a decisive role in B-cell differentiation.1 In lymphomas derived from mature B cells, the expression of PAX5 is maintained at high expression levels in virtually all instances. An exception to this rule is the classical Hodgkin lymphoma (cHL) which—although derived in almost all instances from germinal center B cells—displays a variable and mostly very weak PAX5 expression in the vast majority of cases as compared with normal B cells.2 In addition, the expression of many B-cell-specific antigens is absent or strongly reduced in cHL, whereas genes from other hematopoietic lineages are upregulated.3 Because PAX5 plays a central role in the maintenance of the B-cell phenotype4, 5 we reasoned, if re-constitution of PAX5 expression in a cHL-derived cell line would be able to reactivate the PAX5-driven expression of B-cell genes.

To determine the impact of PAX5 reexpression, we performed gene expression analysis (Affymetrix Human Gene 1.0 ST Array, Affymetrix Inc., Santa Clara, CA, USA) with RNA derived from L428 cells with and without PAX5 overexpression as well as from B-cell lines as controls. Initially, special attention was given to a set of 68 genes3 known to be differentially expressed in B-cell and Hodgkin samples. Based on these 68 genes, there was no reexpression of B-cell-related genes or reduction of Hodgkin-characteristic genes detectable (Figure 1c, left panel). Real-time RT-PCR was additionally carried out for a limited set of B-cell genes (CD19, CD79A, BLNK and BLK; Supplementary Figure S2). However no reactivation of these genes was detectable by this quantitative assay despite strong PAX5 expression (Figure 1a) in the mifepristone-induced L428-PAX5 cells. Extension of the bioinformatic analysis to the global transcriptomic scale revealed a significant PAX5-related upregulation of 535 genes without statistical significance for any KEGG pathway or biological process. In contrast, the 415 downregulated genes were involved in JAK-STAT signaling, the regulation of cell activation/proliferation and apoptosis/cell death. In essence, this clearly indicates that PAX5 is unable to reconstitute the B-cell phenotype in Hodgkin cells despite overexpression, nuclear localization and promoter activity of PAX5.

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Acknowledgements

We thank Hedwig Lammert and Erika Berg for their excellent technical assistance, Maria Joosten and Rebecca Haberman (Johns Hopkins University, Baltimore, USA) for their help with DNA dot blot analysis. We thank the Deutsche Forschungsgemeinschaft (SFB/Transregio 54, subprojects B04 and B06) for supporting this work.

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Authors and Affiliations

  1. Institute of Pathology, Charité-Universitätsmedizin Berlin, Campus Benjamin Franklin, Berlin, Germany

    L Dimitrova, V Seitz, D Lenze, E Oker, A Sommerfeld & M Hummel

  2. Berlin-Brandenburg Center for Regenerative Therapies, Charité-Universitätsmedizin Berlin, Berlin, Germany

    J Hecht & P Hansen

  3. Institute for Medical Genetics and Human Genetics, Charité-Universitätsmedizin Berlin, Berlin, Germany

    P Hansen

  4. Institute of Pathology, Kiel University (CAU), Kiel, Germany

    M Szczepanowski, L Ma & W Klapper

  5. Department of Hematology, The First Affiliated Hospital of Zhejiang University, Hangzhou, China

    L Ma

  6. Department of Hematology, Oncology and Tumorimmunology, Charité-Universitätsmedizin Berlin, Campus Virchow-Klinikum, Berlin, Germany

    F Jundt

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  1. L Dimitrova
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Dimitrova, L., Seitz, V., Hecht, J. et al. PAX5 overexpression is not enough to reestablish the mature B-cell phenotype in classical Hodgkin lymphoma. Leukemia 28, 213–216 (2014). https://doi.org/10.1038/leu.2013.211

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