| First Author | Moyo TK | Year | 2017 |
| Journal | Oncogene | Volume | 36 |
| Issue | 32 | Pages | 4653-4661 |
| PubMed ID | 28368423 | Mgi Jnum | J:248153 |
| Mgi Id | MGI:5925519 | Doi | 10.1038/onc.2017.95 |
| Citation | Moyo TK, et al. (2017) Myc enhances B-cell receptor signaling in precancerous B cells and confers resistance to Btk inhibition. Oncogene 36(32):4653-4661 |
| abstractText | 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 Emu-myc mouse model, where Myc is overexpressed specifically in B cells, both basal and stimulated BCR signaling were increased in precancerous B lymphocytes from Emu-myc mice compared with wild-type littermates. B cells overexpressing Myc displayed constitutively higher levels of activated CD79alpha, Btk, Plcgamma2 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 Emu-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. |
