Induction of the 5S RNP–Mdm2–p53 ribosomal stress pathway delays the initiation but fails to eradicate established murine acute myeloid leukemia

• Published in: Leukemia Vol. 31; no. 1; pp. 213 - 221
• Main Authors: Jaako, P, Ugale, A, Wahlestedt, M, Velasco-Hernandez, T, Cammenga, J, Lindström, M S, Bryder, D
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.01.2017; Nature Publishing Group
• Subjects: 38/89; 631/67/1990/283/1897; 64/60; Acute myelocytic leukemia; Acute myeloid leukemia; Animals; Apoptosis; Biosynthesis; Bone marrow; Cancer Research; Care and treatment; Cell cycle; Cellular signal transduction; Clinical Medicine; Critical Care Medicine; Development and progression; Evolution; Gene expression; Gene mutation; Genes; Genetic aspects; Health aspects; Hematologi; Hematology; Intensive; Internal Medicine; Kinases; Klinisk medicin; Leukemia; Leukemia, Myeloid, Acute - etiology; Lymphoma; MDM2 protein; Medical and Health Sciences; Medicin och hälsovetenskap; Medicine; Medicine & Public Health; Mice; Mutation; Myc protein; Oncology; original-article; p53 Protein; Perturbation; Proteins; Proto-Oncogene Proteins c-mdm2 - genetics; Proto-Oncogene Proteins c-mdm2 - metabolism; Proto-Oncogene Proteins c-mdm2 - physiology; Ribonucleic acid; Ribonucleoproteins - metabolism; Ribonucleoproteins - physiology; Ribosomal Proteins - deficiency; Ribosomes - metabolism; Ribosomes - physiology; RNA; RNA polymerase; Signal Transduction - physiology; Stem cells; Stress; Stress, Physiological; Therapeutic targets; Tumor Suppressor Protein p53 - metabolism; Tumor Suppressor Protein p53 - physiology; Yeast; United States > US; Sweden; Germany
• ISSN: 0887-6924; 1476-5551; 1476-5551
• DOI: 10.1038/leu.2016.159

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.