Ribosome biogenesis impairment leads to p53-mediated apoptosis and MYC-driven lymphoma regression, independent of protein synthesis lesions.
The impaired ribosome biogenesis checkpoint triggers the selective degradation of anti-apoptotic form of MCL-1 by the proteasome.
MYC-driven B-cell lymphomas are addicted to elevated levels of ribosome biogenesis (RiBi), offering the potential for therapeutic intervention. However, it is unclear whether inhibition of RiBi suppresses lymphomagenesis through decreasing translational capacity and/or through p53-activation mediated by the impaired RiBi checkpoint (IRBC). Here we generated Eμ-Myc lymphoma cells expressing inducible shRNAs to either ribosomal protein (RP)L7a 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 anti-apoptotic MCL-1, indicating the critical role of the IRBC in this mechanism. Strikingly, low concentrations of the FDA-approved anti-cancer drug Actinomycin D (ActD) dramatically prolonged the survival of mice harboring Trp53+/+;Eμ-Myc, but not Trp53-/-;Eμ-Myc, lymphomas providing 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.