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Involvement of Tis11b, an AU-rich binding protein, in induction of apoptosis by rituximab in B cell chronic lymphocytic leukemia cells

Leukemia volume 23, pages 986–989 (2009)Cite this article

B-cell chronic lymphocytic leukemia is the commonest form of leukemia in the Western world, characterized by an accumulation of monoclonal CD5+ B cells in the peripheral blood and lymphoid organs. It is clinically a heterogenous disease with overall variable response to many drugs used either alone or in combination, and is currently untreatable. Rituximab has been successfully applied in the clinic in combination with Fludarabine, or Fludarabine and Dexamethasone, and Mitoxantrone.1, 2 We sought to investigate the mechanisms of Rituximab-induced apoptosis in chronic lymphocytic leukemia cells through the upregulation of AU-rich binding proteins that can target certain mRNAs for degradation.3, 4 We found that 20 μg/ml of Rituximab induced apoptosis when crosslinked with an anti-human Fcγ-specific antibody (referred to as XRituximab), especially at 48 h post-stimulation as measured by either propidium iodide alone or Annexin V–propidium iodide methods, which is in agreement with earlier work.5

Induction of Tis11b protein was also verified through intracellular staining and FACS analysis to somehow quantify the percentage of cells that responded to XRituximab treatment in terms of Tis11b protein induction. This method showed that Tis11b protein was induced in 50–80% of the cells at 3 h post-stimulation in different patients tested, reflecting possibly differences in CD20 expression and efficiency in crosslinking of Rituximab between different patients, or differences at the genetic level involved in the regulation of Tis11b among different patients (Figure 1f). When confocal microscopy analysis was performed, it showed that Tis11b is exclusively localized in the cytoplasm with a diffuse rather than punctuate pattern of staining (data not shown). Cytoplasm is the site where mRNA degradation occurs.

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Acknowledgements

We would like to thank Dr Perry Blackshear and Dr Seth Brook for providing us with the human cDNA for Tis11 used in northern blot analysis. We would also like to thank Dr David Flavell for providing Rituximab and Dr C Moroni for providing anti-Tis11b antibody.

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Authors and Affiliations

  1. Division of Immunology Infection and Inflammatory Disease, King's College London, London, UK

    M Baou, A Muthurania & J J Murphy

  2. Faculty of Health and Social Care Sciences, Kingston University and St George's Hospital Medical School, London, UK

    A Jewell

  3. Department of Haematology, University College Medical School, London, UK

    R G Wickremasinghe & K L Yong

  4. Department of Haematology, Guy's Hospital, King's College London, London, UK

    R Carr

  5. Reproductive Health Endocrinology and Development, King's College London, London, UK

    P Marsh

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Correspondence to M Baou.

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

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Baou, M., Jewell, A., Muthurania, A. et al. Involvement of Tis11b, an AU-rich binding protein, in induction of apoptosis by rituximab in B cell chronic lymphocytic leukemia cells. Leukemia 23, 986–989 (2009). https://doi.org/10.1038/leu.2008.340

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