Nucleophosmin: A versatile molecule associated with hematological malignancies

Abstract

Nucleophosmin (NPM) is a nucleolar phosphoprotein that plays multiple roles in ribosome assembly and transport, cytoplasmicnuclear trafficking, centrosome duplication and regulation of p53. In hematological malignancies, the NPM1 gene is frequently involved in chromosomal translocation, mutation and deletion. The NPM1 gene on 5q35 is translocated with the anaplastic lymphoma kinase (ALK) gene in anaplastic large cell lymphoma with t(2;5). The MLF1 and RARA genes are fused with NPM1 in myelodysplastic syndrome and acute myeloid leukemia (AML) with t(3;5) and acute promyelocytic leukemia with t(5;17), respectively. In each fused protein, the Nterminal NPM portion is associated with oligomerization of a partner protein leading to altered signal transduction or transcription. Recently, mutations of exon 12 have been found in a significant proportion of de novo AML, especially in those with a normal karyotype. Mutant NPM is localized aberrantly in the cytoplasm, but the molecular mechanisms for leukemia remain to be studied. N ucleophosmin (NPM), also called B23, numatrin or NO38, was isolated as an abundant nucleolar phosphoprotein, whose expression level is increased significantly by several kinds of stimulation and transformation. (1,2) In 1989, a human NPM cDNA encoding a 294-amino-acid protein was cloned. (3) In 2002, a shorter isoform encoding a 259-amino acid protein that differs at the C-terminus was also isolated. (4) The NPM1 gene spans 25 kb, contains 12 exons and maps to chromosome 5q35. (4,5) Exon 8 is frequently skipped, and exon 10 is used only for the short isoform. Although the biological significance of the short isoform remains unclear, its expression is increased in radiation-insensitive cell lines and the product is localized in the cytoplasm as well as in the nucleus. (4,6) The structural features of NPM consist of an oligomerization domain, a metalbinding motif, a bipartite nuclear localization signal, two Asp/ Glu-rich domains, phosphorylation sites for CDK2 and a nucleor localization signal. (6,7) NPM1 has been recognized by oncologists as a partner gene for various chromosomal translocations: NPM-anaplastic lymphoma kinase (ALK) in anaplastic large cell lymphoma (ALCL) with t(3;5), NPM-RARA in acute promyelocytic leukemia (APL) with t(5;17), and NPM-MLF1 in acute myeloid leukemia (AML)/ myelodysplastic syndrome (MDS) with t(3;5). (8)(9)(10) (Fig. 1, 2) In each chimeric gene product, the N-terminal NPM portion is thought to act as the interface for oligomerization and oncogenic conversion of the C-terminal functional domain such as a kinase or transcription factor. Recently, NPM was associated with centrosome duplication and the regulation of p53, (11,12) and might have a role as a tumor suppressor. Expression and function of NPMNucleophosmin is an abundant and ubiquitously expressed phosphoprotein. It is located mainly in the nucleolus and shuttles between the nucleus and cytoplasm. (13,14) NPM has been proposed to be associated with the synthesis and processing of ribosomal RNA (rRNA), regu...

Ribosomopathies: human disorders of ribosome dysfunction

“…107 NPM1 has also been shown to be mutated in up to 60% of normal karyotype adult AML 107 and to be involved in certain cases of anaplastic large cell lymphoma, MDS, and acute promyelocytic leukemia. 108 NPM1 is an abundant protein located in the nucleolus and functions as an RNA-binding nucleolar phosphoprotein involved in preribosomal assembly. It also serves as a shuttle between the nucleoplasm and the cytoplasm for both nucleic acids and proteins.…”

Nucleophosmin interacts directly with c-Myc and controls c-Myc-induced hyperproliferation and transformation

“…This action of NPM has led some investigators to designate NPM as a tumor suppressor, but determining its role and mechanism of action in tumor suppression has been complex and controversial (3,15,16). The loss of NPM causes genomic instability, likely due to its role in centrosome duplication, which results in increased susceptibility to oncogenic transformation (3).…”

NSC348884, a nucleophosmin inhibitor disrupts oligomer formation and induces apoptosis in human cancer cells

“…However, overexpression of NPM leads to the inhibition of apoptotic cell death (Ye, 2005;Grisendi et al, 2006). In addition, NPM is frequently found in chromosomal translocations associated with hematological malignancies (Naoe et al, 2006). The role of NPM as an oncogene is further enhanced as it binds several tumor suppressor genes, including pRb (Takemura et al, 1999), p14 ARF (Brady et al, 2004;Zhang, 2004;Lee et al, 2005;Gjerset, 2006) and p53 (Colombo et al, 2002;Li et al, 2004;Maiguel et al, 2004).…”