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Chronic Lymphocytic Leukemia

Aberrant O-GlcNAcylation characterizes chronic lymphocytic leukemia

Leukemia volume 24, pages 1588–1598 (2010)Cite this article

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Abstract

O-linked N-Acetylglucosamine (O-GlcNAc) post-translational modifications originate from the activity of the hexosamine pathway, and are known to affect intracellular signaling processes. As aberrant responses to microenvironmental signals are a feature of chronic lymphocytic leukemia (CLL), O-GlcNAcylated protein levels were measured in primary CLL cells. In contrast to normal circulating and tonsillar B cells, CLL cells expressed high levels of O-GlcNAcylated proteins, including p53, c-myc and Akt. O-GlcNAcylation in CLL cells increased following activation with cytokines and through toll-like receptors (TLRs), or after loading with hexosamine pathway substrates. However, high baseline O-GlcNAc levels were associated with impaired signaling responses to TLR agonists, chemotherapeutic agents, B cell receptor crosslinking and mitogens. Indolent and aggressive clinical behavior of CLL cells were found to correlate with higher and lower O-GlcNAc levels, respectively. These findings suggest that intracellular O-GlcNAcylation is associated with the pathogenesis of CLL, which could potentially have therapeutic implications.

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Acknowledgements

This work was supported by Grants from the Ontario Institute of Cancer Research (OICR no. 07Nov-61)), the Canadian Institutes of Health Research (CIHR) (no. 190633) and the Leukemia and Lymphoma Society of Canada (to DS), a Camille Dreyfus Teacher-Scholar award (no. TC-03-009) (to SW), CIHR Grants MOP-79405 and MOP-43938 and a Grant from Genome Canada through the Ontario Genomics Institute (to JWD), Grants NCI R01CA42486 and NIDDK R01 DK61671 (to GWH) and CIHR Grant no. 15095 (to JPD). We thank Dimitar Efremov, Mark Minden and Suzanne Kamel-Reid for helpful discussions.

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  1. Y Shi and J Tomic: These authors contributed equally to this work.

Authors and Affiliations

  1. Division of Molecular and Cellular Biology, Research Institute, Sunnybrook Health Sciences Center, Toronto, Ontario, Canada

    Y Shi, J Tomic, F Wen, S Shaha, A Bahlo, R Harrison & D E Spaner

  2. Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada

    J Tomic & D E Spaner

  3. Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada

    J W Dennis & R Williams

  4. Department of Microbiology and Molecular Genetics, Harvard Medical School, Boston, MA, USA

    B J Gross & S Walker

  5. Department of Biochemistry and Molecular Biology, Immunology Research Group, University of Calgary, Calgary, Ontario, Canada

    J Zuccolo & J P Deans

  6. Department of Biological Chemistry, Johns Hopkins University, School of Medicine, Baltimore, MD, USA

    G W Hart

  7. Department of Medical Oncology, Sunnybrook Odette Cancer Center, Toronto, Ontario, Canada

    D E Spaner

  8. Department of Medicine, University of Toronto, Toronto, Ontario, Canada

    D E Spaner

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Correspondence to D E Spaner.

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Shi, Y., Tomic, J., Wen, F. et al. Aberrant O-GlcNAcylation characterizes chronic lymphocytic leukemia. Leukemia 24, 1588–1598 (2010). https://doi.org/10.1038/leu.2010.152

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