Disease relevance of NPM1

• Clinical characteristics and prognostic implications of NPM1 mutations in acute myeloid leukemia [1].
• Anaplastic large-cell lymphomas (ALCLs) carry chromosome translocations in which the anaplastic lymphoma kinase (ALK) gene is fused to several partners, most frequently, the NPM1 gene [2].
• Thus, the NPM1 mutation is a frequent abnormality in AML patients without known genetic marker; the mutation may represent a new target to monitor minimal residual disease in AML and a potential candidate for alternative and targeted treatments [3].
• This findings suggest that haploinsufficiency of NPM1 may play a role in subtypes of myelodysplasias and leukemias [4].
• In hematological malignancies, the NPM1 gene is frequently involved in chromosomal translocation, mutation and deletion [5].
• As dysregulated homeobox gene expression is also a feature of MLL-rearranged leukemia, the gene expression signatures of NPM1-mutated and MLL-rearranged leukemias were compared [6].

Psychiatry related information on NPM1

• Lewis (Cognition 71 (1999) B23) suggested that a parsimonious explanation would be that it is the total number of times a word has been encountered that predicts reaction times [7].

High impact information on NPM1

• An anti-NPM/B23 antibody, which blocks this phosphorylation, suppresses the initiation of centrosome duplication in vivo [8].
• Moreover, expression of a nonphosphorylatable mutant NPM/ B23 in cells effectively blocks centrosome duplication [8].
• Two rare variants of APL have been described, in which RARA is fused to one of two other genes, PLZF and NPM [9].
• Here we show by gene targeting that Stat3 is required for the transformation of mouse embryonic fibroblasts in vitro, for the development of B-cell lymphoma in transgenic mice and for the growth and survival of both human and mouse NPM-ALK-transformed B and T cells [10].
• Fusion of a kinase gene, ALK, to a nucleolar protein gene, NPM, in non-Hodgkin's lymphoma [11].

Chemical compound and disease context of NPM1

• The expression of two specific nucleolar antigens, p120 and B23, has been investigated in the prostatic carcinoma cell line LNCaP as well as in 40 frozen and 40 formalin-fixed tissue samples of benign and malignant prostatic lesions (15 benign hyperplasias, 5 grade 1, 15 grade 2, and 5 grade 3 carcinomas) [12].
• Anaplastic large-cell lymphoma (ALCL) is frequently associated with the 2;5 translocation and expresses the NPM-ALK fusion protein, which possesses a constitutive tyrosine kinase activity [13].
• Two-dimensional gel electrophoresis analyses identify nucleophosmin as an estrogen regulated protein associated with acquired estrogen-independence in human breast cancer cells [14].

Biological context of NPM1

• The assignment with chromosome banding techniques of the breakpoints of the recurrent translocation t(3;5) which leads to NPM1/MLF1 gene fusion in myeloid malignancies has not been unequivocal [4].
• Studies of knock-out mice have revealed new aspects regarding NPM1 as a tumor-suppressor gene [5].
• The Treg phenotype of the affected cells is strictly dependent on NPM/ALK expression and function as demonstrated by transfection of the kinase into BaF3 cells and inhibition of its enzymatic activity and expression in ALK+TCL cells [15].
• Flow cytometric analysis revealed that wortmannin-treated NPM-ALK-transformed cell lines underwent apoptosis [16].
• Moreover, we show that NPM is a substrate for the UV-activated protein kinase ATR and inhibits the UV-induced p53 phosphorylation at Ser15 [17].

Anatomical context of NPM1

• These findings identify a mechanism of NPM/ALK-mediated oncogenesis based on induction of the Treg phenotype of the transformed CD4(+) T cells [15].
• We also showed that a mutant p80 lacking the NPM portion was unable to transform NIH 3T3 cells [18].
• In agreement, Src-kinase inhibitors or pp60(c-src) siRNA significantly decreased the proliferation rate of NPM-ALK-positive ALCL cell lines [19].
• Primary murine bone marrow retrovirally transduced with NPM-ALK showed a transformed phenotype that was reversible on treatment with PI 3-kinase inhibitors [16].
• Our data show that NPM-ALK gene transcripts are identified in a subpopulation of ALCL, almost exclusively in T or null cell in origin, and in rare cases of HD [20].

Associations of NPM1 with chemical compounds

• The kinase activity and the tyrosine 418 of NPM-ALK are required for its association with Src-kinases [19].
• In transcriptional assays using a retinoic acid response element reporter construct, both NPM-RAR fusion proteins act as retinoic acid-dependent transcriptional activators [21].
• We have studied the effect of 17-allylamino,17-demethoxygeldanamycin (17-AAG), a benzoquinone ansamycin, on NPM-ALK steady-state level in ALCL cells [22].
• B23/nucleophosmin serine 4 phosphorylation mediates mitotic functions of polo-like kinase 1 [23].
• Phosphoprotein profiling by Kinetworks trade mark analysis of M-phase-arrested HeLa cells by nocodazole treatment revealed that a novel mitosis-specific phosphorylation event occurred in the nucleolar protein B23/nucleophosmin at a conserved Ser-4 residue [23].
• Suppression of NPM by RNA interference alleviates the repression of gene expression mediated by retinoic acid and AP2alpha [24].

Physical interactions of NPM1

• NPM binds to the p53 N terminus and inhibits p53 transcriptional activity by more than 70% [17].
• NPM interacts with N-terminal fragments of BRCA1 and BARD1 in a manner dependent upon BRCA1-BARD1 heterodimer formation [25].
• Cellular stress signals liberate ARF from the nucleolus where it is bound to B23/nucleophosmin [26].
• Sedimentation gradient experiments revealed that NPM-ALK forms in vivo multimeric complexes of approximately 200 kDa or greater that also contain normal NPM [27].
• However, MNDA did bind the NPM-MLF1 product of the t(3;5) that contains the N-terminal 175 residues of NPM [28].
• B23 distinctively binds Ebp1 isoforms and regulates cell proliferation and survival through p42 and p48, respectively [29].

Enzymatic interactions of NPM1

• In addition, purified recombinant NPM was phosphorylated by activated PKR [30].
• 2. Both subtypes of B23 proteins were phosphorylated during mitosis by cyclin B/cdc2 [31].
• Overexpression of wild-type NPM rescued cells treated with NPM small interference RNA, whereas overexpression of the granzyme M-cleaved form of NPM did not [32].

Co-localisations of NPM1

• The PM-Scl 100 colocalized predominantly with protein B23 [33].

Regulatory relationships of NPM1

• Nucleophosmin regulates the stability and transcriptional activity of p53 [34].
• Kinase assays demonstrated that recombinant NPM inhibited PKR activation in a dose-dependent manner [30].
• Together, our results reveal a molecular mechanism of ARF in regulating ribosome biogenesis and cell proliferation via inhibiting B23, and suggest a nucleolar role of ARF in surveillance of oncogenic insults [35].
• Our results are consistent with the hypothesis that the Ran-Crm1 complex may promote a local enrichment of NPM on centrosomes, thereby preventing centrosome reduplication [36].
• The present cases of ALCL associated with a novel t(1;2)(q25;p23) demonstrate that at least one fusion partner other than NPM can activate the intracytoplasmic domain of the ALK kinase [37].
• SENP3 catalyses desumoylation of NPM1-SUMO2 conjugates in vitro and counteracts ARF-induced modification of NPM1 by SUMO2 in vivo [38].

Other interactions of NPM1

• Fusion of a kinase gene, ALK, to a nucleolar protein gene, NPM, in non-Hodgkin's lymphoma [39].
• NPM/ALK, in turn, induces the phenotype through activation of its key signal transmitter, signal transducer and activator of transcription 3 (STAT3) [15].
• Nucleophosmin sets a threshold for p53 response to UV radiation [17].
• NPM1 mutations were associated with normal karyotype and with internal tandem duplication (ITD) and D835 mutations in FLT3, but not with other mutations [1].
• Co-immunoprecipitation and in vitro binding experiments showed that NPM associated with PKR [30].

Analytical, diagnostic and therapeutic context of NPM1

• These results suggest that the NPM1 mutation is not necessarily an early event during leukemogenesis or that leukemia clones with NPM1 mutations are sensitive to chemotherapy [1].
• Conclusions.-Detection of NPM1 gene mutations may allow dissection of the heterogeneous group of AML with normal karyotype into prognostically different subgroups [40].
• Overall, 6 (3 T and 3 null) of 49 ALCL and 3 (2 nodular sclerosis and 1 mixed cellularity) of 72 HD showed the presence of NPM-ALK transcripts by RT-PCR [20].
• Cell fractionation studies of the t(2;5) translocation-containing lymphoma cell line SUP-M2 showed NPM-ALK to be localized within both the cytoplasmic and nuclear compartments [27].
• Western blotting of one-dimensional and two-dimensional gels showed that the form of nucleophosmin B23 that is up-regulated in melanoma represents a posttranslationally modified form, most likely reflecting enhanced phosphorylation in the tumor-derived cells [41].

References