| First Author | Nam J | Year | 2019 |
| Journal | Leukemia | Volume | 33 |
| Issue | 12 | Pages | 2912-2923 |
| PubMed ID | 31138843 | Mgi Jnum | J:282626 |
| Mgi Id | MGI:6378812 | Doi | 10.1038/s41375-019-0492-y |
| Citation | Nam J, et al. (2019) Disruption of the Myc-PDE4B regulatory circuitry impairs B-cell lymphoma survival. Leukemia 33(12):2912-2923 |
| abstractText | A large body of evidence suggests that B-cell lymphomas with enhanced Myc expression are associated with an aggressive phenotype and poor prognosis, which makes Myc a compelling therapeutic target. Phosphodiesterase 4B (PDE4B), a main hydrolyzer of cyclic AMP (cAMP) in B cells, was shown to be involved in cell survival and drug resistance in diffuse large B cell lymphomas (DLBCL). However, the interrelationship between Myc and PDE4B remains unclear. Here, we first demonstrate the presence of the Myc-PDE4B feed-forward loop, in which Myc and PDE4B mutually reinforce the expression of each other. Next, the combined targeting of Myc and PDE4 synergistically prevented the proliferation and survival of B lymphoma cells in vitro and in a mouse xenograft model. We finally recapitulated this combinatorial effect in Emu-myc transgenic mice; co-inhibition of Myc and PDE4 suppressed lymphomagenesis and restored B cell development to the wild type level that was associated with marked reduction in Myc levels, unveiling the critical role of the Myc-PDE4B amplification loop in the regulation of Myc expression and the pathogenesis of B cell lymphoma. These findings suggest that the disruption of the Myc-PDE4B circuitry can be exploited in the treatment of B cell malignancies. |
