Defective ribosome assembly impairs leukemia progression in a murine model of acute myeloid leukemia
Daniel Sjövall,
Sudip Ghosh,
Narcis Fernandez-Fuentes,
Talia Velasco-Hernandez,
Anna Hogmalm,
Pablo Menendez,
Jenny Hansson,
Carolina Guibentif,
Pekka Jaako
Affiliations
Daniel Sjövall
Sahlgrenska Center for Cancer Research, Department of Microbiology and Immunology, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, 40530 Gothenburg, Sweden
Sudip Ghosh
Department of Experimental Medical Science, Lund Stem Cell Center, Lund University, Lund, Sweden
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
Anna Hogmalm
Sahlgrenska Center for Cancer Research, Department of Microbiology and Immunology, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, 40530 Gothenburg, Sweden
Pablo Menendez
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
Jenny Hansson
Department of Experimental Medical Science, Lund Stem Cell Center, Lund University, Lund, Sweden
Carolina Guibentif
Sahlgrenska Center for Cancer Research, Department of Microbiology and Immunology, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, 40530 Gothenburg, Sweden
Pekka Jaako
Sahlgrenska Center for Cancer Research, Department of Microbiology and Immunology, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, 40530 Gothenburg, Sweden; Corresponding author
Summary: 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.
