Publication Date
10-1-2024
Journal
EJHaem
DOI
10.1002/jha2.996
PMID
39415917
PMCID
PMC11481009
PubMedCentral® Posted Date
8-20-2024
PubMedCentral® Full Text Version
Post-print
Published Open-Access
yes
Keywords
acute leukemia, cell biology, transcription
Abstract
BACKGROUND:NPM1‐mutated acute myeloid leukemia (AML) is the most frequent AML subtype. As wild‐type NPM1 is known to orchestrate ribosome biogenesis, it has been hypothesized that altered translation may contribute to leukemogenesis and leukemia maintenance in NPM1‐mutated AML. However, this hypothesis has never been investigated. We reasoned that if mutant NPM1 (NPM1c) directly impacts translation in leukemic cells, loss of NPM1c would result in acute changes in the ribosome footprint.
METHODS: Here, we performed ribosome footprint profiling (Ribo-seq) and bulk messenger RNA (mRNA) sequencing in two
RESULTS AND DISCUSSION: Incubation of degron cells with the small compound dTAG-13 enables highly specific degradation of NPM1c within 4 hours. As expected, RNA-sequencing data showed early loss of homeobox gene expression following NPM1c degradation, confirming the reliability of our model. In contrast, Ribo-seq data showed negligible changes in the ribosome footprint in both cell lines, implying that the presence of NPM1c does not influence ribosome abundance and positioning on mRNA. While it is predictable that NPM1c exerts its leukemogenic activity at multiple levels, ribosome footprint does not seem influenced by the presence of mutant NPM1.
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Biological Phenomena, Cell Phenomena, and Immunity Commons, Hematology Commons, Hemic and Lymphatic Diseases Commons, Life Sciences Commons, Medical Cell Biology Commons, Medical Microbiology Commons, Medical Molecular Biology Commons, Neoplasms Commons, Oncology Commons
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