Defective ribosome assembly impairs leukemia progression in a murine model of acute myeloid leukemia
Despite an advanced understanding of disease mechanisms, the current therapeutic regimen fails to cure most patients with acute myeloid leukemia (AML). In the present study, we address the role of ribosome assembly in leukemia cell function. We apply patient datasets and murine models to demonstrate that immature leukemia cells in mixed-lineage leukemia-rearranged AML are characterized by relatively high ribosome biogenesis and protein synthesis rates. Using a model with inducible regulation of ribosomal subunit joining, we show that defective ribosome assembly extends survival in mice with AML. Single-cell RNA sequencing and proteomic analyses reveal that leukemia cell adaptation to defective ribosome assembly is associated with an increase in ribosome biogenesis and deregulation of the transcription factor landscape. Finally, we demonstrate that defective ribosome assembly shows antileukemia efficacy in p53-deficient AML. Our study unveils the critical requirement of a high protein synthesis rate for leukemia progression and highlights ribosome assembly as a therapeutic target in AML.
Authors
- Pablo Menéndez (ORCID: https://orcid.org/0000-0001-9372-1007)
- Pekka Jaako (ORCID: https://orcid.org/0000-0003-3587-8318)
- Sudip Ghosh (ORCID: https://orcid.org/0000-0001-8277-0639)
- Anna Hogmalm
- Jenny Hansson (ORCID: https://orcid.org/0000-0001-9174-8089)
- Talía Velasco-Hernández (ORCID: https://orcid.org/0000-0003-2183-7443)
- Carolina Guibentif (ORCID: https://orcid.org/0000-0003-1056-9922)
- Daniel Sjövall (ORCID: https://orcid.org/0000-0002-3491-2740)
- Narcís Fernández‐Fuentes (ORCID: https://orcid.org/0000-0002-6421-1080)
Institutions
- Institució Catalana de Recerca i Estudis Avançats (ES)
- Lund University (SE)
- Sahlgrenska University Hospital (SE)
- Josep Carreras Leukaemia Research Institute (ES)
- Spanish Clinical Research Network (ES)
- University of Gothenburg (SE)
Publication Details
- Journal
- Cell Reports
- Published
- 2024-10-16
- DOI
- https://doi.org/10.1016/j.celrep.2024.114864
- Citations
- 6
- Primary Topic
- RNA modifications and cancer
- Type
- article
- Field-Weighted Citation Impact
- 1.40
Funders
- Åke Wiberg Stiftelse
- Jeanssons Stiftelser
- Leuka
- Mary Béves Stiftelse för Barncancerforskning
- Gunvor och Josef Anérs Siftelse
- Vetenskapsrådet
- Stiftelsen Assar Gabrielssons Fond
- José Carreras Leukämie-Stiftung
- Sahlgrenska Universitetssjukhuset
- Barncancerfonden
- Science for Life Laboratory
- Sahlgrenska Akademin