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

Moyo TK, Wilson CS, Moore DJ, Eischen CM
Oncogene. 2017 36 (32): 4653-4661

PMID: 28368423 · PMCID: PMC5552428 · DOI:10.1038/onc.2017.95

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.

MeSH Terms (23)

Agammaglobulinaemia Tyrosine Kinase Animals B-Lymphocytes CD79 Antigens Cell Proliferation Flow Cytometry Humans Lymphoma, Non-Hodgkin Male Mice Mice, Inbred C57BL Mitogen-Activated Protein Kinase 3 Phosphatidylinositol 3-Kinases Phospholipase C gamma Phosphorylation Precancerous Conditions Protein-Tyrosine Kinases Proto-Oncogene Proteins c-myc Pyrazoles Pyrimidines Receptors, Antigen, B-Cell Splenic Neoplasms Syk Kinase

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