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RelB, together with RelA, sustains cell survival and confers proteasome inhibitor sensitivity of chronic lymphocytic leukemia cells from bone marrow

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Abstract

Although the biological factors that contribute to the pathogenesis of chronic lymphocytic leukemia (CLL) remain widely unresolved, it has been suggested that dysregulated cell survival and proliferation are fundamental to this process. Constitutive classical nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) activation protects CLL B-cells from cell death and plays a critical role in the acquisition of chemoresistance. RelB, representing the alternative NF-κB activity, functions specifically in lymphoid organogenesis and B-cell maturation. RelB indeed plays a tumor-supportive role and confers radiation resistance in tumors. However, the involvement of RelB in CLL has not been addressed. Here, we analyzed the NF-κB activation in 67 of CLL bone marrow (BM). Both the RelA and RelB activity were detected in CLL B-cells from BM, in spite of inevitable variability. Low RelB activity was linked to a favorable prognosis of CLL. The migration and adhesion abilities of CLL B-cells were not affected by the RelB activity. High RelB activity, together with the RelA activity, maintained basal survival of cells. The induction of RelA and RelB expression in the nucleus was responsible for better survival of CLL B-cells supported by bone marrow stromal cells. In addition, the presence of high RelB activity in CLL B-cells was correlated with sensitivity to proteasome inhibitor but not fludarabine. Taken together, we provided evidences that not only RelA but also RelB, subunits of NF-κB family, played an important role in the cellular behaviors of CLL cells from BM. The strength of RelB activity influenced the prognosis of CLL patients.

Key message

  • RelB, with RelA activity, maintained the basal survival of CLL cells from BM.

  • RelB, with RelA, conferred the proteasome inhibitor sensitivity of CLL cells.

  • Induction of RelA and RelB was responsible for the better survival of CLL B-cells.

  • The strength of RelB activity influenced the prognosis of CLL patients.

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Acknowledgments

We greatly acknowledge Jinlan Pan and Minqing Zhu for excellent technical assistance and suggestions. This work was supported by Jiangsu Provincial Natural Science Foundation of China (F.G., grant no. BK2011306), and National Natural Science Foundation of China (F.G., grant no. 81070405 and 81172433).

Authorship contribution statement

J.J.X performed research, collected, and analyzed data. P.Z. performed research. W.J.W performed research. A.N.S. collected clinical information. F.G. designed and performed research, collected, analyzed and interpreted data, and wrote the manuscript.

Conflict of interest statement

The authors declare that they have no conflicts of interest.

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  1. Wenjuan Wang

    Present address: Shandong University Qilu Hospital Research Center for Cell Therapy, Key Laboratory of Cardiovascular Remodeling and Function Research, Qilu Hospital of Shandong University, Wenhuaxi Road 44, Jinan, China, 250012

Authors and Affiliations

  1. Central Lab, The First Affiliated Hospital of Soochow University, Shizi Road 188, Suzhou, China, 215006

    Jingjing Xu, Peng Zhou, Wenjuan Wang & Feng Guo

  2. Dept. of Hematology, Jiangsu Institute of Hematology, The First Affiliated Hospital of Soochow University, Shizi Road 188, Suzhou, China, 215006

    Aining Sun

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  1. Jingjing Xu
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Xu, J., Zhou, P., Wang, W. et al. RelB, together with RelA, sustains cell survival and confers proteasome inhibitor sensitivity of chronic lymphocytic leukemia cells from bone marrow. J Mol Med 92, 77–92 (2014). https://doi.org/10.1007/s00109-013-1081-6

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