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

Leukemia. 2019 Dec;33(12):2912-2923. doi: 10.1038/s41375-019-0492-y. Epub 2019 May 28.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Biomarkers, Tumor
  • Cell Line, Tumor
  • Cyclic AMP / metabolism
  • Cyclic Nucleotide Phosphodiesterases, Type 4 / genetics*
  • Cyclic Nucleotide Phosphodiesterases, Type 4 / metabolism
  • Disease Models, Animal
  • Gene Expression Regulation, Neoplastic*
  • Humans
  • Immunohistochemistry
  • Lymphoma, B-Cell / genetics*
  • Lymphoma, B-Cell / metabolism
  • Lymphoma, B-Cell / mortality*
  • Lymphoma, B-Cell / pathology
  • Lymphoma, Large B-Cell, Diffuse / genetics
  • Lymphoma, Large B-Cell, Diffuse / metabolism
  • Lymphoma, Large B-Cell, Diffuse / mortality
  • Lymphoma, Large B-Cell, Diffuse / pathology
  • Mice, Transgenic
  • Prognosis
  • Protein Binding
  • Proto-Oncogene Proteins c-myc / genetics*
  • Proto-Oncogene Proteins c-myc / metabolism


  • Biomarkers, Tumor
  • Proto-Oncogene Proteins c-myc
  • Cyclic AMP
  • Cyclic Nucleotide Phosphodiesterases, Type 4
  • PDE4B protein, human