Author:
Sjövall Daniel,Ghosh Sudip,Hansson Jenny,Guibentif Carolina,Jaako Pekka
Abstract
ABSTRACTDespite the 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 protein synthesis control in AML leukemia stem cell (LSC) function and leukemia propagation. We apply a murine model of mixed-lineage leukemia-rearranged AML to demonstrate that LSCs are characterized by high global protein synthesis rate. Using a genetic model that permits inducible and graded regulation of ribosomal subunit joining, we show that defective ribosome assembly leads to a significant survival advantage by selectively eradicating LSCs but not normal hematopoietic stem and progenitor cells. Finally, transcriptomic and proteomic analyses identify a rare subset of LSCs with immature stem cell signature and high ribosome content that promotes the resistance to defective ribosome assembly. Collectively, our study unveils a critical requirement of high protein synthesis rate for LSC function and highlights ribosome assembly as a therapeutic target in AML.
Publisher
Cold Spring Harbor Laboratory
Cited by
1 articles.
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