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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

Jaako, P. LU ; Ugale, A. LU ; Wahlestedt, M. LU ; Velasco, Talia LU ; Cammenga, J. LU ; Lindström, M. S. LU and Bryder, D. LU (2017) In Leukemia 31(1). p.213-221
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... (More)

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.Leukemia advance online publication, 17 June 2016; doi:10.1038/leu.2016.159.

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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Leukemia
volume
31
issue
1
pages
213 - 221
publisher
Nature Publishing Group
external identifiers
  • Scopus:84975136191
ISSN
0887-6924
DOI
10.1038/leu.2016.159
language
English
LU publication?
yes
id
f36cdd56-de28-43ed-a2e4-92eeb5c67e2f
date added to LUP
2016-07-11 12:38:53
date last changed
2017-01-13 16:21:16
@article{f36cdd56-de28-43ed-a2e4-92eeb5c67e2f,
  abstract     = {<p>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.Leukemia advance online publication, 17 June 2016; doi:10.1038/leu.2016.159.</p>},
  author       = {Jaako, P. and Ugale, A. and Wahlestedt, M. and Velasco, Talia and Cammenga, J. and Lindström, M. S. and Bryder, D.},
  issn         = {0887-6924},
  language     = {eng},
  number       = {1},
  pages        = {213--221},
  publisher    = {Nature Publishing Group},
  series       = {Leukemia},
  title        = {Induction of the 5S RNP–Mdm2–p53 ribosomal stress pathway delays the initiation but fails to eradicate established murine acute myeloid leukemia},
  url          = {http://dx.doi.org/10.1038/leu.2016.159},
  volume       = {31},
  year         = {2017},
}