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Myc enhances B-cell receptor signaling in precancerous B cells and confers resistance to Btk inhibition

Oncogene volume 36, pages 4653–4661 (2017)Cite this article

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Abstract

Dysregulation of the oncogenic transcription factor MYC induces B-cell transformation and is a driver for B-cell non-Hodgkin lymphoma (B-NHL). MYC overexpression in B-NHL is associated with more aggressive phenotypes and poor prognosis. Although genomic studies suggest a link between MYC overexpression and B-cell receptor (BCR) signaling molecules in B-NHL, signaling pathways essential to Myc-mediated B-cell transformation have not been fully elucidated. We utilized intracellular phospho-flow cytometry to investigate the relationship between Myc and BCR signaling in pre-malignant B cells. Utilizing the Eμ-myc mouse model, where Myc is overexpressed specifically in B cells, both basal and stimulated BCR signaling were increased in precancerous B lymphocytes from Eμ-myc mice compared with wild-type littermates. B cells overexpressing Myc displayed constitutively higher levels of activated CD79α, Btk, Plcγ2 and Erk1/2. Notably, Myc-overexpressing B cells maintained elevated BCR signaling despite treatment with ibrutinib, a Bruton’s tyrosine kinase inhibitor. Furthermore, PI3K/Akt pathway signaling was also increased in Eμ-myc B cells, and this increase was partially suppressed with ibrutinib. In addition, experiments with Btk-null B cells revealed off-target effects of ibrutinib on BCR signaling. Our data show that in pre-malignant B cells, Myc overexpression is sufficient to activate BCR and PI3K/Akt signaling pathways and further enhances signaling following BCR ligation. Therefore, our results indicate that precancerous B cells have already acquired enhanced survival and growth capabilities before transformation, and that elevated MYC levels confer resistance to pharmacologic inhibitors of BCR signaling, which has significant implications for B-NHL treatment.

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Acknowledgements

We thank Dr Peggy Kendall for providing Btk−/− mice and members of the Eischen laboratory and Dr Jonathan Irish for their advice. This work was supported by NIH/NCI R21CA184352 (CME), the Hematology Helping Hands Research Award (TKM) and the NCI Cancer Center support grant P30CA68485 that supports the Vanderbilt Flow Cytometry Shared Resource and the NCI Cancer Center support grant P30CA056036.

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Authors and Affiliations

  1. Department of Medicine, Division of Hematology/Oncology, Vanderbilt University Medical Center, Nashville, TN, USA

    T K Moyo

  2. Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA

    C S Wilson, D J Moore & C M Eischen

  3. Department of Pediatrics, Vanderbilt University Medical Center, Nashville, TN, USA

    D J Moore

  4. Department of Cancer Biology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, USA

    C M Eischen

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Correspondence to C M Eischen.

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Moyo, T., Wilson, C., Moore, D. et al. Myc enhances B-cell receptor signaling in precancerous B cells and confers resistance to Btk inhibition. Oncogene 36, 4653–4661 (2017). https://doi.org/10.1038/onc.2017.95

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