Impaired ribosome biogenesis checkpoint activation induces p53-dependent MCL-1 degradation and MYC-driven lymphoma death

• DOI: 10.1182/blood.2020007452
• Publication Date: 2021-01-14T22:01:40Z
• Authors: Ana Domostegui; Suresh Peddigari; Carol A. Mercer; Flavia Iannizzotto; Marta L. Rodriguez; Marta Garcia-Cajide; Virginia Amador; Sarah T. Diepstraten; Gemma L. Kelly; Ramón Salazar; Sara C. Kozma; Eric P. Kusnadi; Jian Kang; Antonio Gentilella; Richard B. Pearson; George Thomas; Joffrey Pelletier
• Keywords: Male; Ribosomal Proteins; Lymphoma, B-Cell; Cell Cycle Checkpoints; Proto-Oncogene Proteins c-myc; Mice; Cell Line, Tumor; Proteolysis; Dactinomycin; Animals; Myeloid Cell Leukemia Sequence 1 Protein; RNA, Neoplasm; RNA, Small Interfering; Tumor Suppressor Protein p53; Ribosomes

AbstractMYC-driven B-cell lymphomas are addicted to increased levels of ribosome biogenesis (RiBi), offering the potential for therapeutic intervention. However, it is unclear whether inhibition of RiBi suppresses lymphomagenesis by decreasing translational capacity and/or by p53 activation mediated by the impaired RiBi checkpoint (IRBC). Here we generated Eμ-Myc lymphoma cells expressing inducible short hairpin RNAs to either ribosomal protein L7a (RPL7a) or RPL11, the latter an essential component of the IRBC. The loss of either protein reduced RiBi, protein synthesis, and cell proliferation to similar extents. However, only RPL7a depletion induced p53-mediated apoptosis through the selective proteasomal degradation of antiapoptotic MCL-1, indicating the critical role of the IRBC in this mechanism. Strikingly, low concentrations of the US Food and Drug Administration–approved anticancer RNA polymerase I inhibitor Actinomycin D (ActD) dramatically prolonged the survival of mice harboring Trp53+/+;Eμ-Myc but not Trp53–/–;Eμ-Myc lymphomas, which provides a rationale for treating MYC-driven B-cell lymphomas with ActD. Importantly, the molecular effects of ActD on Eμ-Myc cells were recapitulated in human B-cell lymphoma cell lines, highlighting the potential for ActD as a therapeutic avenue for p53 wild-type lymphoma.