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Chronic Lymphocytic Leukemia

Selective, novel spleen tyrosine kinase (Syk) inhibitors suppress chronic lymphocytic leukemia B-cell activation and migration

Leukemia volume 26, pages 1576–1583 (2012)Cite this article

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Abstract

Syk is a protein tyrosine kinase that couples B-cell receptor (BCR) activation with downstream signaling pathways, affecting cell survival and proliferation. Moreover, Syk is involved in BCR-independent functions, such as B-cell migration and adhesion. In chronic lymphocytic leukemia (CLL), Syk becomes activated by external signals from the tissue microenvironment, and was targeted in a first clinical trial with R788 (fostamatinib), a relatively nonspecific Syk inhibitor. Here, we characterize the activity of two novel, highly selective Syk inhibitors, PRT318 and P505-15, in assays that model CLL interactions with the microenvironment. PRT318 and P505-15 effectively antagonize CLL cell survival after BCR triggering and in nurse-like cell-co-cultures. Moreover, they inhibit BCR-dependent secretion of the chemokines CCL3 and CCL4 by CLL cells, and leukemia cell migration toward the tissue homing chemokines CXCL12, CXCL13, and beneath stromal cells. PRT318 and P505-15 furthermore inhibit Syk and extracellular signal-regulated kinase phosphorylation after BCR triggering. These findings demonstrate that the selective Syk inhibitors PRT318 and P505-15 are highly effective for inhibition of CLL survival and tissue homing circuits, and support the therapeutic development of these agents in patients with CLL, other B-cell malignancies and autoimmune disorders.

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Acknowledgements

The study was supported by CLL Global Research Foundation grants (to WGW and JAB), and a Cancer Prevention and Research Institute of Texas (CPRIT) grant (to JAB).

Author Contributions

JH performed the experiments, analyzed the data, designed the figures, and wrote the paper with JAB; GPC, US and AP performed immunoblots, synthesized and biologically characterized the compounds, helped with the experimental design and reviewed the paper; MS assisted with the experiments and reviewed the paper; AF, FR, WGW, MJK, and SOB provided samples, helped with data interpretation and reviewed the paper; and JAB designed the research, supervised the study, analyzed the data and revised the paper.

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Authors and Affiliations

  1. Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    J Hoellenriegel, M Sivina, A Ferrajoli, F Ravandi, W G Wierda, S O'Brien, M J Keating & J A Burger

  2. Portola Pharmaceuticals, Inc., South San Francisco, CA, USA

    G P Coffey, U Sinha & A Pandey

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  1. J Hoellenriegel
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Correspondence to J A Burger.

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JH, MS, AF, FR, WGW, MJK, SOB and JAB declare no conflict of interest. GPC, US and AP are employees and shareholders of Portola Pharmaceuticals.

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Hoellenriegel, J., Coffey, G., Sinha, U. et al. Selective, novel spleen tyrosine kinase (Syk) inhibitors suppress chronic lymphocytic leukemia B-cell activation and migration. Leukemia 26, 1576–1583 (2012). https://doi.org/10.1038/leu.2012.24

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