title: Induction of the 5S RNP-Mdm2-p53 ribosomal stress pathway delays the initiation but fails to eradicate established murine acute myeloid leukemia.
abstract: 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.
authors.affiliation: Division of Molecular Hematology, Lund Stem Cell Center, Lund University, Lund, Sweden.
authors.forename: P
authors.initials: P
authors.lastname: Jaako
authors.affiliation: Division of Molecular Hematology, Lund Stem Cell Center, Lund University, Lund, Sweden.
authors.forename: A
authors.initials: A
authors.lastname: Ugale
authors.affiliation: Division of Molecular Hematology, Lund Stem Cell Center, Lund University, Lund, Sweden.
authors.forename: M
authors.initials: M
authors.lastname: Wahlestedt
authors.affiliation: Division of Molecular Hematology, Lund Stem Cell Center, Lund University, Lund, Sweden.
authors.forename: T
authors.identifier: 0000-0003-2183-7443
authors.initials: T
authors.lastname: Velasco-Hernandez
authors.affiliation: Department of Hematology, Linköping University Hospital, Linköping, Sweden.
authors.forename: J
authors.initials: J
authors.lastname: Cammenga
authors.affiliation: Department of Medical Biochemistry and Biophysics, SciLifeLab, Karolinska Institute, Stockholm, Sweden.
authors.forename: M S
authors.initials: MS
authors.lastname: Lindström
authors.affiliation: Division of Molecular Hematology, Lund Stem Cell Center, Lund University, Lund, Sweden.
authors.forename: D
authors.initials: D
authors.lastname: Bryder
mesh_terms: D000818:Animals; D015470:Leukemia, Myeloid, Acute / Q000209:etiology*; D051379:Mice; D051736:Proto-Oncogene Proteins c-mdm2 / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D012261:Ribonucleoproteins / Q000378:metabolism / Q000502:physiology; D012269:Ribosomal Proteins / Q000172:deficiency; D012270:Ribosomes / Q000378:metabolism / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*; D013312:Stress, Physiological; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism / Q000502:physiology
chemical_list: D012261:Ribonucleoproteins; D012269:Ribosomal Proteins; D016159:Tumor Suppressor Protein p53; C040343:ribosomal protein S19; C497207:Mdm2 protein, mouse; D051736:Proto-Oncogene Proteins c-mdm2