Induction of the 5S RNP-Mdm2-p53 ribosomal stress pathway delays the initiation but fails to eradicate established murine acute myeloid leukemia
2017 (English)In: Leukemia, ISSN 0887-6924, E-ISSN 1476-5551, Vol. 31, no 1, 213-221 p.Article in journal (Refereed) Published
Mutations resulting in constitutive activation of signaling pathways that regulate ribosome biogenesis are among the most common genetic events in acute myeloid leukemia (AML). However, whether ribosome biogenesis presents as a therapeutic target to treat AML remains unexplored. Perturbations in ribosome biogenesis trigger the 5S ribonucleoprotein particle (RNP)-Mdm2-p53 ribosomal stress pathway, and induction of this pathway has been shown to have therapeutic efficacy in Myc-driven lymphoma. In the current study we address the physiological and therapeutic role of the 5S RNP-Mdm2-p53 pathway in AML. By utilizing mice that have defective ribosome biogenesis due to downregulation of ribosomal protein S19 (Rps19), we demonstrate that induction of the 5S RNP-Mdm2-p53 pathway significantly delays the initiation of AML. However, even a severe Rps19 deficiency that normally results in acute bone marrow failure has no consistent efficacy on already established disease. Finally, by using mice that harbor a mutation in the Mdm2 gene disrupting its binding to 5S RNP, we show that loss of the 5S RNP-Mdm2-p53 pathway is dispensable for development of AML. Our study suggests that induction of the 5S RNP-Mdm2-p53 ribosomal stress pathway holds limited potential as a single-agent therapy in the treatment of AML.
Place, publisher, year, edition, pages
NATURE PUBLISHING GROUP , 2017. Vol. 31, no 1, 213-221 p.
IdentifiersURN: urn:nbn:se:liu:diva-136370DOI: 10.1038/leu.2016.159ISI: 000394058700027PubMedID: 27256803OAI: oai:DiVA.org:liu-136370DiVA: diva2:1087796
Funding Agencies|Swedish Childrens Cancer Society; Crafoord Foundation; Gunnar Nilsson Cancer Foundation; Swedish Research Council; Swedish Cancer Society; ERC Consolidator grant 2017-04-102017-04-102017-04-10