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

Area of Science:

• Oncology
• Molecular Biology
• Cancer Therapeutics

Background:

• MYC-driven B-cell lymphomas rely on ribosome biogenesis (RiBi) for growth.
• The role of RiBi inhibition in suppressing lymphomagenesis, specifically via translational capacity or p53 activation through the impaired RiBi checkpoint (IRBC), is not fully understood.

Purpose of the Study:

• To investigate whether inhibiting RiBi suppresses lymphomagenesis by decreasing translational capacity or by p53 activation mediated by the IRBC.
• To determine the therapeutic potential of Actinomycin D (ActD) in MYC-driven B-cell lymphomas.

Main Methods:

• Generated Eμ-Myc lymphoma cells with inducible short hairpin RNAs targeting ribosomal protein L7a (RPL7a) or RPL11.
• Assessed the impact of RPL7a and RPL11 depletion on RiBi, protein synthesis, cell proliferation, and apoptosis.
• Administered Actinomycin D (ActD) to mice with Trp53+/+;Eμ-Myc and Trp53-/-;Eμ-Myc lymphomas.
• Evaluated ActD's molecular effects in human B-cell lymphoma cell lines.

Main Results:

• Loss of either RPL7a or RPL11 reduced RiBi, protein synthesis, and proliferation similarly.
• RPL7a depletion induced p53-mediated apoptosis via selective proteasomal degradation of MCL-1, highlighting the IRBC's role.
• ActD significantly prolonged survival in mice with Trp53+/+;Eμ-Myc lymphomas but not Trp53-/-;Eμ-Myc lymphomas.
• ActD's effects on Eμ-Myc cells were replicated in human B-cell lymphoma cell lines.

Conclusions:

• The impaired RiBi checkpoint (IRBC) is critical for p53-mediated apoptosis in MYC-driven lymphomas.
• Actinomycin D (ActD) demonstrates therapeutic potential for p53 wild-type MYC-driven B-cell lymphomas by selectively targeting MCL-1 and inducing apoptosis.