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Defective ribosome assembly impairs leukemia progression in a murine model of acute myeloid leukemia

Sjövall, Daniel LU ; Ghosh, Sudip LU ; Fernandez-Fuentes, Narcis ; Velasco-Hernandez, Talia ; Hogmalm, Anna ; Menendez, Pablo ; Hansson, Jenny LU orcid ; Guibentif, Carolina LU and Jaako, Pekka LU (2024) In Cell Reports 43(11).
Abstract

Despite an advanced understanding of disease mechanisms, the current therapeutic regimen fails to cure most patients with acute myeloid leukemia (AML). In the present study, we address the role of ribosome assembly in leukemia cell function. We apply patient datasets and murine models to demonstrate that immature leukemia cells in mixed-lineage leukemia-rearranged AML are characterized by relatively high ribosome biogenesis and protein synthesis rates. Using a model with inducible regulation of ribosomal subunit joining, we show that defective ribosome assembly extends survival in mice with AML. Single-cell RNA sequencing and proteomic analyses reveal that leukemia cell adaptation to defective ribosome assembly is associated with an... (More)

Despite an advanced understanding of disease mechanisms, the current therapeutic regimen fails to cure most patients with acute myeloid leukemia (AML). In the present study, we address the role of ribosome assembly in leukemia cell function. We apply patient datasets and murine models to demonstrate that immature leukemia cells in mixed-lineage leukemia-rearranged AML are characterized by relatively high ribosome biogenesis and protein synthesis rates. Using a model with inducible regulation of ribosomal subunit joining, we show that defective ribosome assembly extends survival in mice with AML. Single-cell RNA sequencing and proteomic analyses reveal that leukemia cell adaptation to defective ribosome assembly is associated with an increase in ribosome biogenesis and deregulation of the transcription factor landscape. Finally, we demonstrate that defective ribosome assembly shows antileukemia efficacy in p53-deficient AML. Our study unveils the critical requirement of a high protein synthesis rate for leukemia progression and highlights ribosome assembly as a therapeutic target in AML.

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author
; ; ; ; ; ; ; and
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
CP: Cancer
in
Cell Reports
volume
43
issue
11
article number
114864
publisher
Cell Press
external identifiers
  • pmid:39412990
  • scopus:85207347423
ISSN
2639-1856
DOI
10.1016/j.celrep.2024.114864
language
English
LU publication?
yes
additional info
Publisher Copyright: © 2024 The Author(s)
id
406b4683-1467-4905-a70b-4dc1a1d0f352
date added to LUP
2024-11-26 10:45:29
date last changed
2025-07-09 18:16:28
@article{406b4683-1467-4905-a70b-4dc1a1d0f352,
  abstract     = {{<p>Despite an advanced understanding of disease mechanisms, the current therapeutic regimen fails to cure most patients with acute myeloid leukemia (AML). In the present study, we address the role of ribosome assembly in leukemia cell function. We apply patient datasets and murine models to demonstrate that immature leukemia cells in mixed-lineage leukemia-rearranged AML are characterized by relatively high ribosome biogenesis and protein synthesis rates. Using a model with inducible regulation of ribosomal subunit joining, we show that defective ribosome assembly extends survival in mice with AML. Single-cell RNA sequencing and proteomic analyses reveal that leukemia cell adaptation to defective ribosome assembly is associated with an increase in ribosome biogenesis and deregulation of the transcription factor landscape. Finally, we demonstrate that defective ribosome assembly shows antileukemia efficacy in p53-deficient AML. Our study unveils the critical requirement of a high protein synthesis rate for leukemia progression and highlights ribosome assembly as a therapeutic target in AML.</p>}},
  author       = {{Sjövall, Daniel and Ghosh, Sudip and Fernandez-Fuentes, Narcis and Velasco-Hernandez, Talia and Hogmalm, Anna and Menendez, Pablo and Hansson, Jenny and Guibentif, Carolina and Jaako, Pekka}},
  issn         = {{2639-1856}},
  keywords     = {{CP: Cancer}},
  language     = {{eng}},
  month        = {{11}},
  number       = {{11}},
  publisher    = {{Cell Press}},
  series       = {{Cell Reports}},
  title        = {{Defective ribosome assembly impairs leukemia progression in a murine model of acute myeloid leukemia}},
  url          = {{http://dx.doi.org/10.1016/j.celrep.2024.114864}},
  doi          = {{10.1016/j.celrep.2024.114864}},
  volume       = {{43}},
  year         = {{2024}},
}