Npm1 Conditional Knockout mouse models

Npm1 encodes the mouse ortholog of human NPM1, a pentameric nucleolar phosphoprotein that shuttles between nucleolus, nucleoplasm, and cytoplasm, chaperoning ribosomal proteins and histones, controlling ribosome biogenesis, and stabilizing ARF and p53 through nucleolar sequestration. The defining leukemogenic lesion is not loss but a frameshift in the terminal exon, most often the type A tetranucleotide duplication at W288, which ablates the C-terminal tryptophans and creates a new leucine-rich nuclear export signal, producing cytoplasmic NPM1c, sustained HOX program expression, and XPO1 dependence in acute myeloid leukemia. Because homozygous deletion is embryonic lethal with hematopoietic and midline defects while heterozygotes show genomic instability, design is explicit: humanized exon 12 frameshift knockins interrogate NPM1c leukemia and menin or exportin inhibitor response, whereas conditional nulls test nucleolar stress and ribosome biogenesis dependence. Paralogs Npm2 and Npm3 do not substitute functionally, and a cooperating Flt3 internal tandem duplication allele markedly shortens latency.

Conditional deletion of Npm1 limits the genetic change to the lineage you choose. That helps in oncology, immunology, and metabolic work where systemic loss would muddy the read. After you confirm Cre specificity, crossing to Npm1 floxed stock yields usable cohorts.