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

Domostegui, A; Peddigari, S; Mercer, CA; Iannizzotto, F; Rodriguez, ML; Garcia-Cajide, M; Amador, V; Diepstraten, ST; Kelly, GL; Salazar, R; Kozma, SC; Kusnadi, EP; Kang, J; Gentilella, A; Pearson, RB; Thomas, G; Pelletier, J

Author(s): Domostegui, A; Peddigari, S; Mercer, CA; Iannizzotto, F; Rodriguez, ML; Garcia-Cajide, M; Amador, V; Diepstraten, ST; Kelly, GL; Salazar, R; Kozma, SC; Kusnadi, EP; Kang, J; Gentilella, A; Pearson, RB; Thomas, G; Pelletier, J;
Details: Publication Year 2021-06-17,Volume 137,Issue #24,Page 3351-3364
Journal Title: Blood
Abstract: MYC-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 Emu-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+/+;Emu-Myc but not Trp53-/-;Emu-Myc lymphomas, which provides a rationale for treating MYC-driven B-cell lymphomas with ActD. Importantly, the molecular effects of ActD on Emu-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.
Keywords: Animals; Cell Cycle Checkpoints/*drug effects/genetics; Cell Line, Tumor; Dactinomycin/*pharmacology; *Lymphoma, B-Cell/drug therapy/genetics/metabolism; Male; Mice; *Myeloid Cell Leukemia Sequence 1 Protein/genetics/metabolism; Proteolysis/*drug effects; *Proto-Oncogene Proteins c-myc/genetics/metabolism; RNA, Neoplasm/genetics/metabolism; RNA, Small Interfering/genetics/metabolism; Ribosomal Proteins/antagonists & inhibitors/genetics/metabolism; *Ribosomes/genetics/metabolism; *Tumor Suppressor Protein p53/genetics/metabolism
Research Division(s): Blood Cells And Blood Cancer
PubMed ID: 33512431
Publisher's Version: https://doi.org/10.1182/blood.2020007452
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Creation Date: 2022-02-08 02:27:51

Last Modified: 2022-02-08 02:30:20