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Disruption of the Myc-PDE4B regulatory circuitry impairs B-cell lymphoma survival

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Author(s)
Jehyun NamDong Uk KimEungyoung KimBomi KwakMin Ji KoAh-Young OhBum-Joon ParkYea Woon KimAeRi KimYoungmi JungJae-Hoon LeeHo-Jin ShinInmyoung ParkDae-Kyu SongJee-Yeong JeongYun-Han LeeSang-Woo KimHokeun Sun
Keimyung Author(s)
Song, Dae KyuLee, Yun Han
Department
Dept. of Physiology (생리학)
Dept. of Molecular Medicine (분자의학)
Journal Title
Leukemia
Issued Date
2019
Abstract
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.
Keimyung Author(s)(Kor)
송대규
이윤한
Publisher
School of Medicine (의과대학)
Citation
Jehyun Nam et al. (2019). Disruption of the Myc-PDE4B regulatory circuitry impairs B-cell lymphoma survival. Leukemia. doi: 10.1038/s41375-019-0492-y
Type
Article
ISSN
1476-5551
Source
https://www.nature.com/articles/s41375-019-0492-y
DOI
10.1038/s41375-019-0492-y
URI
https://kumel.medlib.dsmc.or.kr/handle/2015.oak/42020
Appears in Collections:
1. School of Medicine (의과대학) > Dept. of Molecular Medicine (분자의학)
1. School of Medicine (의과대학) > Dept. of Physiology (생리학)
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