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Induction of the 5S RNP-Mdm2-p53 ribosomal stress pathway delays the initiation but fails to eradicate established murine acute myeloid leukemia
Lund University, Sweden.
Lund University, Sweden.
Lund University, Sweden.
Lund University, Sweden.
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2017 (English)In: Leukemia, ISSN 0887-6924, E-ISSN 1476-5551, Vol. 31, no 1, 213-221 p.Article in journal (Refereed) Published
Abstract [en]

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.
National Category
Hematology
Identifiers
URN: urn:nbn:se:liu:diva-136370DOI: 10.1038/leu.2016.159ISI: 000394058700027PubMedID: 27256803OAI: oai:DiVA.org:liu-136370DiVA: diva2:1087796
Note

Funding Agencies|Swedish Childrens Cancer Society; Crafoord Foundation; Gunnar Nilsson Cancer Foundation; Swedish Research Council; Swedish Cancer Society; ERC Consolidator grant [615068]

Available from: 2017-04-10 Created: 2017-04-10 Last updated: 2017-04-10

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Cammenga, Jörg
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Division of Surgery, Orthopedics and OncologyFaculty of Medicine and Health Sciences
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CiteExportLink to record
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Cite
Citation style
  • apa
  • harvard1
  • ieee
  • modern-language-association-8th-edition
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