2. Academic Validation
  3. Defective ribosome assembly impairs leukemia progression in a murine model of acute myeloid leukemia

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

  • Cell Rep. 2024 Oct 15;43(11):114864. doi: 10.1016/j.celrep.2024.114864.
Daniel Sjövall 1,  Sudip Ghosh 2,  Narcis Fernandez-Fuentes 3,  Talia Velasco-Hernandez 4,  Anna Hogmalm 1,  Pablo Menendez 5,  Jenny Hansson 2,  Carolina Guibentif 1,  Pekka Jaako 6
Affiliations

Affiliations

  • 1 Sahlgrenska Center for Cancer Research, Department of Microbiology and Immunology, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, 40530 Gothenburg, Sweden.
  • 2 Department of Experimental Medical Science, Lund Stem Cell Center, Lund University, Lund, Sweden.
  • 3 Josep Carreras Leukemia Research Hospital, Campus Clinic, Barcelona, Spain; Spanish Cell Therapy Network (TERAV), ISCIII, Barcelona, Spain.
  • 4 Josep Carreras Leukemia Research Hospital, Campus Clinic, Barcelona, Spain; Spanish Cell Therapy Network (TERAV), ISCIII, Barcelona, Spain; Department of Biomedicine, University of Barcelona, Barcelona, Spain.
  • 5 Josep Carreras Leukemia Research Hospital, Campus Clinic, Barcelona, Spain; Spanish Cell Therapy Network (TERAV), ISCIII, Barcelona, Spain; Department of Biomedicine, University of Barcelona, Barcelona, Spain; Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain; Spanish Cancer Research Network (CIBERONC), ISCIII, Barcelona, Spain.
  • 6 Sahlgrenska Center for Cancer Research, Department of Microbiology and Immunology, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, 40530 Gothenburg, Sweden. Electronic address: pekka.jaako@gu.se.
PMID: 39412990 DOI: 10.1016/j.celrep.2024.114864
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 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.

Keywords

AML; CP: Cancer; MLL; eIF6; leukemia; leukemia stem cell; mRNA translation; protein synthesis; ribosome; scRNA-seq.

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