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Fostamatinib inhibits B-cell receptor signaling, cellular activation and tumor proliferation in patients with relapsed and refractory chronic lymphocytic leukemia

Leukemia volume 27, pages 1769–1773 (2013)Cite this article

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Chronic lymphocytic leukemia (CLL) is characterized by the expansion of monoclonal, mature CD5+/CD23+ B cells.1 In addition, small lymphocytic lymphoma (SLL) shares the biological characteristics of CLL; however, it is distinguished from CLL based on not exceeding 5000 clonal B-lymphocytes per μl. Here we use the term CLL throughout to denote both CLL and SLL.

A role of antigen signaling in the pathogenesis of CLL has been inferred from the observation that CLL cells use a restricted repertoire of immunoglobulin heavy chain variable (IGHV) genes, which encode antigen binding domains of the B-cell receptor (BCR),2 and that many CLL cases express virtually identical BCRs, so-called ‘stereotyped BCRs’, that could recognize shared antigens.3 Furthermore, clinical disease progression is predicted by whether the expressed IGHV gene has undergone somatic hypermutation (M-CLL) or not (U-CLL).1 The U-CLL subtype is more rapidly progressive and often expresses ZAP-70, a tyrosine kinase essential for T-cell receptor signaling, which has been shown to enhance BCR signaling in vitro.4 In addition, our recent demonstration of inducible activation of the BCR and NF-κB pathways in CLL cells in the lymph node indicating that antigen-dependent BCR signaling continues throughout the disease course.5 Although both CLL subtypes showed evidence of antigen signaling in vivo, the more progressive U-CLL subtype had stronger BCR activation, higher expression of MYC and increased proliferation, suggesting that BCR signaling may contribute to clinical progression. These data indicate that BCR signaling likely has a pivotal role in the pathogenesis of CLL.

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Acknowledgements

This research was supported and funded by the Intramural Research Program of the National, Heart, Lung and Blood Institute. This work was supported in part by the University of Rochester SPORE in lymphoma P50 CA13080503 and the James P Wilmot Foundation. PMB is a Lymphoma Research Foundation Clinical Investigator.

Author contributions

SEMH planned the research, performed experiments and analyzed data. PMB analyzed patient data. EMM was involved in planning components of the research and supported experiments. DL performed statistical analysis. AW and JWF planned and supervised the research and analyzed data. All authors assisted in the writing of this paper and approved the final version of the manuscript.

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Author notes

  1. S E M Herman and P M Barr: SEMH and PMB are co-first authors.

  2. A Wiestner and J W Friedberg: AW and JWF are co-senior authors.

Authors and Affiliations

  1. Hematology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA

    S E M Herman, E M McAuley, D Liu & A Wiestner

  2. Department of Medicine, School of Medicine and Dentistry, University of Rochester, Rochester, NY

    P M Barr & J W Friedberg

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  1. S E M Herman
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  4. D Liu
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  6. J W Friedberg
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Corresponding authors

Correspondence to A Wiestner or J W Friedberg.

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Competing interests

JWF is a scholar in Clinical Research of the Leukemia and Lymphoma Society. JWF received research support from Rigel for the clinical trial and subsequent analysis. The remaining authors declare no conflict of interest.

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Herman, S., Barr, P., McAuley, E. et al. Fostamatinib inhibits B-cell receptor signaling, cellular activation and tumor proliferation in patients with relapsed and refractory chronic lymphocytic leukemia. Leukemia 27, 1769–1773 (2013). https://doi.org/10.1038/leu.2013.37

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