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 Eμ-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.
Myc and PDE4B activate expression of each other, forming a positive feedback loop.
Co-inhibition of Myc and PDE4 induces synergistic killing of B lymphoma cells.
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pcDNA-Myc construct is a gift from Dr. Dongchul Kang (Hallym University, Korea) and Ly10 DLBCL cell line was kindly provided by Dr. Yoon Kyung Jeon (Seoul National University Hospital, Korea). This work was supported by Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Science, ICT & Future Planning (NRF-2013R1A1A2008838 and NRF-2016R1A2B4011758) to S-WK and (NRF-2014R1A5A2010008 and 2018R1A2B2007410) to Y-HL. IP was a recipient of the research fund 2018 through Youngsan University.
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Nam, J., Kim, D., Kim, E. et al. Disruption of the Myc-PDE4B regulatory circuitry impairs B-cell lymphoma survival. Leukemia 33, 2912–2923 (2019) doi:10.1038/s41375-019-0492-y