Downregulation of rRNA synthesis by BCL-2 induces chemoresistance in diffuse large B cell lymphoma
Overexpression of the antiapoptotic oncogene <i>BCL-2</i> predicts poor prognosis in diffuse large B cell lymphoma (DLBCL) treated with anthracycline-based chemoimmunotherapy. Anthracyclines exert antitumor effects by multiple mechanisms including inhibition of ribosome biogenesis (RiBi) through rRNA synthesis blockade. RiBi inhibitors induce p53 stabilization through the ribosomal proteins-MDM2-p53 pathway, with stabilized p53 levels depending on baseline rRNA synthesis rate. We found that the BH3-mimetic venetoclax could not fully reverse BCL-2-mediated resistance to RiBi inhibitors in DLBCL cells. BCL-2 overexpression was associated with decreased baseline rRNA synthesis rate, attenuating p53 stabilization by RiBi inhibitors. Drugs stabilizing p53 irrespective of RiBi inhibition reversed BCL-2-induced resistance <i>in vitro</i> and <i>in vivo</i>, restoring p53 activation and apoptosis. A small nucleolar size, indicative of low baseline rRNA synthesis, correlated with high BCL-2 levels and poor outcomes in DLBCL patients. These findings uncover alternative BCL-2-dependent chemoresistance mechanisms, providing a rationale for specific combination strategies in BCL-2 positive lymphomas.
Authors
- Umberto Vitolo (ORCID: https://orcid.org/0000-0001-7772-2747)
- Enrico Derenzini (ORCID: https://orcid.org/0000-0002-7154-8140)
- Marianna Penzo (ORCID: https://orcid.org/0000-0002-1738-9767)
- Alessandro Davini (ORCID: https://orcid.org/0009-0004-8504-3604)
- Giovanna Motta (ORCID: https://orcid.org/0000-0001-5593-5397)
- Roberto Chiarle (ORCID: https://orcid.org/0000-0003-1564-8531)
- Simone Zanetti
- Stefania Orecchioni (ORCID: https://orcid.org/0000-0002-6781-7002)
- Claudio Agostinelli (ORCID: https://orcid.org/0000-0001-6702-4312)
- Giovanna Talarico (ORCID: https://orcid.org/0000-0001-5051-6468)
- Domenico Salemi (ORCID: https://orcid.org/0000-0002-2688-4145)
- Elena Baiardi (ORCID: https://orcid.org/0000-0002-5432-4751)
- Chiara Corsini (ORCID: https://orcid.org/0000-0002-3129-0157)
- Paolo Falvo (ORCID: https://orcid.org/0000-0001-5743-5046)
- Valentina Tabanelli (ORCID: https://orcid.org/0000-0002-4142-2248)
- Corrado Tarella (ORCID: https://orcid.org/0000-0003-1473-6046)
- Angelica Calleri
- Saveria Mazzara (ORCID: https://orcid.org/0000-0003-1799-2360)
- Francesco Bertolini (ORCID: https://orcid.org/0000-0001-5660-3255)
- Davide Treré (ORCID: https://orcid.org/0000-0003-1127-1052)
- Maria Rosaria Sapienza (ORCID: https://orcid.org/0000-0002-1078-2128)
- Stefano Pileri
- Claudio Ceccarelli (ORCID: https://orcid.org/0000-0003-0743-2087)
- Pier Luigi Zinzani (ORCID: https://orcid.org/0000-0002-2112-2651)
- Anna Rossi
- Federica Melle
Institutions
- Boston Children's Hospital (US)
- University of Milan (IT)
- IFOM (IT)
- Azienda USL di Bologna (IT)
- Candiolo Cancer Institute (IT)
- University of Turin (IT)
- European Institute of Oncology (IT)
- Bocconi University (IT)
- University of Bologna (IT)
Publication Details
- Journal
- iScience
- Published
- 2025-04-03
- DOI
- https://doi.org/10.1016/j.isci.2025.112333
- Citations
- 5
- Primary Topic
- Lymphoma Diagnosis and Treatment
- Type
- article
- Field-Weighted Citation Impact
- 7.36