NPM1 encodes a phosphoprotein involved in diverse cellular processes such as ribosome biogenesis, centrosome duplication, protein chaperoning, histone assembly, cell proliferation, and regulation of tumor suppressors TP53/p53 and ARF. NPM1 protein binds ribosome presumably to drive ribosome nuclear export. It associates with nucleolar ribonucleoprotein structures and bind single-stranded nucleic acids. It acts as a chaperonin for the core histones H3, H2B and H4.
NPM1 somatic mutations have been observed in haematopoietic/lymphoid tissue and in bile duct tumors. Mutations in the form of nucleotide insertions in exon 12 of NPM1 are found in 25-35% of all cases of AML. Most NPM1 mutations occur in exon 12. They generate an extra nuclear export signal motif and cause loss of tryptophan 288 and 290 (or tryptophan 290 alone); as a result, NPM1 accumulates aberrantly in the cytoplasm. Because NPM1 is thought to possess a tumor-suppressor function, any disruption in its cellular localization may be critical for malignant transformation.
NPM1 is involved in fusions with ALK in anaplasic large cell lymphoma (ALCL), a form of high-grade non-Hodgkin lymphoma. Translocation t(2;5)(p23;q35) gives rise to NPM1-ALK. The resulting chimeric NPM1-ALK protein homodimerize and the kinase becomes constitutively activated. ALK+ ALCL represent 50 to 60 % of ALCL cases.
The t(2;5)(p23;q35) translocation is also observed in inflammatory myofibroblastic tumor
NPM1 is involved in fusions with RARA in a form of acute promyelocytic leukemia (AML-M3). Translocation t(5;17)(q32;q11) gives rise to NPM1-RARA.
NPM1 is involved in fusions with MLF1 in AML, myelodysplastic syndrome, chronic myelogenous leukemia in blast crisis (BC-CML). Translocation t(3;5)(q25;q34) gives rise to NPM1-MLF1.
References (open access)
Translocations and mutations involving the nucleophosmin (NPM1) gene in lymphomas and leukemias. Falini B, Nicoletti I, Bolli N, Martelli MP, Liso A, Gorello P, Mandelli F, Mecucci C, Martelli MF. Haematologica. 2007 Apr;92(4):519-32.