Aberrant subcellular expression of nucleophosmin and NPM-MLF1 fusion protein in acute myeloid leukaemia carrying t(3;5): A comparison with NPMc+ AML

Falini, Brunangelo; Bigerna, Barbara; Pucciarini, Alessandra; Tiacci, Enrico; Mecucci, Cristina; Morris, Stephan W.; Bolli, Niccolò; Rosati, Roberto; Hanissian, Silva H.; Ma, Zhigui; Sun, Yi; Colombo, Emanuela; Arber, Daniel A.; Pacini, Roberta; Starza, Roberta La; Galletti, B; Liso, Arcangelo; Martelli, Maria Paola; Diverio, Daniela; Pelicci, Pier Giuseppe; Coco, Francesco Lo; Martelli, Massimo F.

doi:10.1038/sj.leu.2404068

Cited by 46 publications

(54 citation statements)

References 10 publications

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“…Like ALCL with t(2;5), AML with t(3;5) shows aberrant nucleophosmin expression in cytoplasm as, due to its MLF1 moiety, the NPM1-MLF1 fusion protein localizes in leukaemic cell cytoplasm. 51 However, unlike ALCL with t(2;5), NPM1wt is also dislocated into cytoplasm of AML cells carrying the t(3;5) 51 through a mechanism that still needs to be deciphered.…”

Section: Nucleophosmin Traffic Is Perturbed In Lymphomas and Leukaemimentioning

confidence: 99%

Altered nucleophosmin transport in acute myeloid leukaemia with mutated NPM1: molecular basis and clinical implications

et al. 2009

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Nucleophosmin (NPM1) is a highly conserved nucleo-cytoplasmic shuttling protein that shows a restricted nucleolar localization. Mutations of NPM1 gene leading to aberrant cytoplasmic dislocation of nucleophosmin (NPMc þ ) occurs in about one third of acute myeloid leukaemia (AML) patients that exhibit distinctive biological and clinical features. We discuss the latest advances in the molecular basis of nucleophosmin traffic under physiological conditions, describe the molecular abnormalities underlying altered transport of nucleophosmin in NPM1-mutated AML and present evidences supporting the view that cytoplasmic nucleophosmin is a critical event for leukaemogenesis. We then outline how a highly specific immunohistochemical assay can be exploited to diagnose NPM1-mutated AML and myeloid sarcoma in paraffin-embedded samples by looking at aberrant nucleophosmin accumulation in cytoplasm of leukaemic cells. This procedure is also suitable for detection of haemopoietic multilineage involvement in bone marrow trephines. Moreover, use of immunohistochemistry as surrogate for molecular analysis can serve as first-line screening in AML and should facilitate implementation of the 2008 World Health Organization classification of myeloid neoplasms that now incorporates AML with mutated NPM1 (synonym: NPMc þ AML) as a new provisional entity. Finally, we discuss the future therapeutic perspectives aimed at reversing the altered nucleophosmin transport in AML with mutated NPM1.

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Section: Nucleophosmin Traffic Is Perturbed In Lymphomas and Leukaemimentioning

confidence: 99%

Altered nucleophosmin transport in acute myeloid leukaemia with mutated NPM1: molecular basis and clinical implications

et al. 2009

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“…Human NPM-MLF1 þ AML cells, in addition to losing one copy of wild-type NPM, also exhibit dislocation of the remaining NPM protein from the nucleolus, its physiological site of action, to the cytoplasm. 13 The cytoplasmic NPMc þ mutation is associated with up to one-third of adult AML and its transgenic expression results in myeloproliferation.…”

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confidence: 99%

NPM-MLF1 synergizes with Npm haploinsufficiency to enhance myeloid progenitor activity

Wh¹,

Salek‐Ardakani²,

Pandolfi

et al. 2011

Leukemia

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“…Immunostaining studies have shown that MLF1 is localized mainly in the cytoplasm, whereas the NPM-MLF1 fusion protein is localized in the nucleus, especially the nucleolus (60) (Fig. 4).…”

Section: Npm-mlf1 Chimeric Protein In Aml/mdsmentioning

confidence: 99%

“…(57) In contrast, NPM-MLF1 and wild-type NPM were stained by using anti-Cterminal NPM antibody. (60) doi : acid residues (VSLRK). Thus, despite the genetic heterogeneity, all of these NPM1 gene mutations have the common feature of a frameshift mutation at the C-terminal region.…”

Section: Frameshift Mutation Of Npm1 In Amlmentioning

confidence: 99%

Nucleophosmin: A versatile molecule associated with hematological malignancies

Naoe

Suzuki

Kiyoi³

et al. 2006

Cancer Science

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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...

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Aberrant subcellular expression of nucleophosmin and NPM-MLF1 fusion protein in acute myeloid leukaemia carrying t(3;5): A comparison with NPMc+ AML

Cited by 46 publications

References 10 publications

Altered nucleophosmin transport in acute myeloid leukaemia with mutated NPM1: molecular basis and clinical implications

Altered nucleophosmin transport in acute myeloid leukaemia with mutated NPM1: molecular basis and clinical implications

NPM-MLF1 synergizes with Npm haploinsufficiency to enhance myeloid progenitor activity

Nucleophosmin: A versatile molecule associated with hematological malignancies

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