Alternative titles; symbols
Other entities represented in this entry:
HGNC Approved Gene Symbol: NPM1
Cytogenetic location: 5q35.1 Genomic coordinates (GRCh38): 5:171,387,116-171,410,900 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 5q35.1 | Leukemia, acute myeloid, somatic | 601626 | 3 |
NPM1 is a ubiquitously expressed nucleolar protein that shuttles between the nucleus and cytoplasm. It is implicated in multiple functions, including ribosomal protein assembly and transport, control of centrosome duplication, and regulation of the tumor suppressor ARF (600160). NPM1 mutations that relocalize NPM1 from the nucleus into the cytoplasm are associated with development of acute myeloid leukemia (AML; 601626) (Garzon et al., 2008).
Chan et al. (1989) reported the nucleotide sequence of a cDNA of human nucleophosmin. The cDNA has a coding sequence equivalent to a protein of 294 amino acids. When protein levels were compared with Western blot immunoassays, Novikoff hepatoma showed 20 times more nucleophosmin than normal, and hypertrophic rat liver showed about 5 times more nucleophosmin than unstimulated normal liver.
Dalenc et al. (2002) developed a HeLa cell line that overexpressed FGF2 (134920) and showed radioresistance following exposure to ionizing radiation. By differential display, they determined that the radioresistant cells upregulated expression of an NPM1 splice variant. This variant, which Dalenc et al. (2002) designated NPM2, encodes a deduced 259-amino acid protein that differs from the original isolate only at the C terminus. Western blot analysis of HeLa cells detected both NPM isoforms, which migrated with apparent molecular masses of 38 and 34 kD. The amount of the shorter isoform increased following FGF2 overexpression.
Chan et al. (1989) found that nucleophosmin is a nucleolar phosphoprotein that is more abundant in tumor cells than in normal resting cells. Stimulation of the growth of normal cells, e.g., mitogen activation of B lymphocytes, was accompanied by an increase in nucleophosmin protein level. They stated that nucleophosmin is likely involved in the assembly of ribosomal proteins into ribosomes. Electron microscopic study indicated that nucleophosmin is concentrated in the granular region of the nucleolus, where ribosome assembly occurs.
Okuda et al. (2000) identified nucleophosmin as a substrate of CDK2 (116953)/cyclin E (123837) in centrosome duplication. NPM1 associated with unduplicated centrosomes, and dissociated from centrosomes by CDK2/cyclin E-mediated phosphorylation. An anti-NPM1 antibody, which blocked this phosphorylation, suppressed the initiation of centrosome duplication in vivo. Moreover, expression of a nonphosphorylatable mutant NPM1 in cells effectively blocked centrosome duplication. Okuda et al. (2000) concluded that NPM1 is a target of CDK2/cyclin E in the initiation of centrosome duplication.
By immunohistochemistry using antibodies that did not differentiate between NPM1 isoforms, Dalenc et al. (2002) found nuclear staining for NPM1 in control HeLa cells and cytoplasmic staining following transfection with FGF2. They concluded that overexpression of FGF2 caused the redistribution of both NPM1 isoforms. By transfection of the C-terminally truncated NPM1 variant (NPM2) into radiosensitive HeLa cells, Dalenc et al. (2002) showed that the radioresistance associated with FGF2 overexpression was mediated by increased expression of this NPM1 isoform.
Using immunohistochemical analysis, Fukawa et al. (2012) detected colocalization of NPM1 with DDX31 (616533) in nucleoli in renal cell carcinoma (RCC; 144700) cell lines. Reciprocal coimmunoprecipitation analysis showed that full-length DDX31 interacted with NPM1 in RCC cells. Knockdown of either DDX31 or NPM1 attenuated preribosomal RNA biogenesis. Knockdown of DDX31 also reduced cell growth, concomitant with translocation of NPM1 from nucleoli to cytoplasm. Cytoplasmic NPM1 bound HDM2 (MDM2; 164785), thereby reducing binding of HDM2 to p53 (TP53; 191170) and causing G1 cell cycle arrest and apoptosis.
Nachmani et al. (2019) found that Npm1 regulated 2-prime-O-methylation of ribosomal RNA (rRNA) in mouse embryonic fibroblasts (MEFs) by interacting with C/D box small nucleolar RNAs (snoRNAs) and the rRNA 2-prime-O-methyltransferase Fbl (134795). Microarray analysis showed that Npm1 deletion in MEFs affected 2-prime-O-methylation sites in 28S rRNA and impaired internal ribosome entry site (IRES) translation through 2-prime-O-methylation regulation. Deletion and overexpression experiments demonstrated that NPM1 also controlled cell growth and differentiation through regulation of 2-prime-O-methylation in K562 human erythroleukemia cells.
NPM1/ALK Fusion Protein
Zhang et al. (2007) stated that ALK (105590) tyrosine kinase expression is normally confined to neural cells, but chromosomal translocations involving ALK and various partners, most frequently NPM1, result in ectopic expression of ALK in a subset of T-cell lymphomas (TCLs) (see CYTOGENETICS). The NPM1/ALK fusion protein contains the NPM1 oligomerization motif and the ALK catalytic domain, is constitutively activated through autophosphorylation, and mediates malignant cell transformation in vitro and in vivo by activating downstream effectors, including STAT3 (102582). Zhang et al. (2007) found that TCL cell lines expressing NPM1/ALK expressed STAT5B (604260), but not STAT5A (601511), protein, whereas normal resting and activated T cells from peripheral blood and ALK-negative TCL cell lines expressed STAT5A protein. Activated NPM1/ALK-positive TCL cell lines also did not express STAT5A mRNA, in spite of having an intact STAT5A gene. Analysis of the CpG island in the STAT5A promoter showed that the region was methylated in NPM1/ALK-positive, but not NPM1/ALK-negative, T cells. Chromatin immunoprecipitation analysis revealed that SP1 (189906) bound the STAT5A promoter in normal activated T cells, whereas MECP2 (300005) bound the promoter of NPM1/ALK-positive TCL cells. Demethylation of the promoter resulted in STAT5A activation and inhibition of NPM1/ALK expression by binding of STAT5A to the NPM1/ALK fusion gene. Expression of NPM1/ALK in NPM1/ALK-negative TCL cells resulted in silencing of STAT5A in a STAT3-dependent manner, whereas small interfering RNA mediated-depletion of NPM1/ALK resulted in STAT5A expression. Zhang et al. (2007) concluded that NPM1/ALK induces epigenetic silencing of the STAT5A gene and that the STAT5A protein can act as a tumor suppressor by inhibiting NPM1/ALK expression.
Dutta et al. (2001) presented the structure of an N-terminal domain of Xenopus nucleoplasmin (Np-core), which is related to NPM1, at 2.3-angstrom resolution. The Np-core monomer is an 8-stranded beta barrel that fits snugly within a stable pentamer. In the crystal, 2 pentamers associate to form a decamer. The authors showed that both Np and Np-core are competent to assemble large complexes that contain the 4 core histones. These complexes each contain 5 histone octamers that dock to a central Np decamer. Dutta et al. (2001) provided models of histone storage, sperm chromatin decondensation, and nucleosome assembly.
Dalenc et al. (2002) stated that the NPM1 gene contains 12 exons.
Gross (2019) mapped the NPM1 gene to chromosome 5q35.1 based on an alignment of the NPM1 sequence (GenBank BC002398) with the genomic sequence (GRCh38).
Large-cell lymphomas comprise approximately 25% of all non-Hodgkin lymphomas in children and young adults. Approximately one-third of these tumors have a t(2;5)(p23;q35) chromosomal translocation, which suggests that rearrangement of cellular protooncogenes on these chromosomes contributes to lymphomagenesis. To clone the genes altered by the t(2;5), Morris et al. (1994) used a positional strategy based on fluorescence in situ hybridization (FISH) ordering of regionally derived cosmid clones. Bidirectional chromosome walks were performed from cosmids approximately 290 kb apart that flanked the breakpoint on chromosome 5; each walk spanned a genomic region of 150 kb. In this way, they showed that the rearrangement fused the NPM nucleolar phosphoprotein gene on 5q35 to a previously unidentified protein tyrosine kinase gene, ALK (105590), on chromosome 2p23. In the predicted hybrid protein, the N-terminus of nucleophosmin was found to be linked to the catalytic domain of ALK. Expressed in the small intestine, testis, and brain but not in normal lymphoid cells, ALK shows greatest sequence similarity to the insulin receptor subfamily of kinases. Unscheduled expression of the truncated ALK may contribute to malignant transformation in these lymphomas. FISH mapping indicated that the NPM and ALK genes are transcribed in centromere-to-telomere orientations on chromosome 5 and 2, respectively, with the 2.4-kb transcript arising from the derivative 5 translocated chromosome. Northern blot analysis provided no evidence for expression of a reciprocal ALK-NPM chimeric transcript.
Acute promyelocytic leukemia (APL; 612376) is uniquely associated with chromosomal translocations that disrupt the gene encoding the retinoic acid receptor, RARA (180240). In more than 99% of cases, this disruption results from the formation of a PML-RARA fusion gene through translocation. Rare variants of APL have been described, in which RARA is fused to 1 of 3 other genes, PLZF (176797), NUMA (164009), and NPM (Redner et al., 1996).
Somatic Mutations
NPM, a nucleocytoplasmic shuttling protein with prominent nucleolar localization, regulates the ARF (103180)/p53 (191170) tumor suppressor pathway. Chromosomal translocations involving the NPM gene cause cytoplasmic dislocation of the NPM protein. Falini et al. (2005) used immunohistochemical methods to study the subcellular localization of NPM in bone marrow biopsy specimens from 591 patients with primary acute myelogenous leukemia (AML; 601626). They then correlated the presence of cytoplasmic NPM with clinical and biologic features of the disease. Cytoplasmic NPM was detected in 35.2% of the 591 specimens from patients with primary AML but not in 135 secondary AML specimens or in 980 hematopoietic or extrahematopoietic neoplasms other than AML. It was associated with a wide spectrum of morphologic subtypes of the disease, a normal karyotype, and responsiveness to induction chemotherapy, but not with recurrent genetic abnormalities. There was a high frequency of internal tandem duplications of FLT3 (136351) and absence of CD34 (142230) and CD133 (604365) in AML specimens with a normal karyotype and cytoplasmic dislocation of NPM, but not in those in which the protein was restricted to the nucleus. AML specimens with cytoplasmic NPM carried mutations in the NPM gene (see 164040.0001-164040.0004); this mutant gene caused cytoplasmic localization of NPM in transfected cells. All 6 NPM mutant proteins showed mutations in at least 1 of the tryptophan residues at positions 288 and 290 and shared the same last 5 amino acid residues (VSLRK). Thus, despite genetic heterogeneity, all NPM gene mutations resulted in a distinct sequence in the NPM protein C terminus. Falini et al. (2005) concluded that cytoplasmic NPM is a characteristic feature of a large subgroup of patients with AML who have a normal karyotype, NPM gene mutations, and responsiveness to induction chemotherapy. Grisendi and Pandolfi (2005) noted that NPM staining in cases of AML with aberrant cytoplasmic localization of the protein is mostly cytoplasmic, which suggests that the mutant NPM acts dominantly on the product of the remaining wildtype allele, causing its retention in the cytoplasm by heterodimerization.
By microRNA (miRNA) expression profiling, Garzon et al. (2008) identified 36 upregulated and 21 downregulated miRNAs in AML patients with NPM1 mutations compared with AML patients without NPM1 mutations. miR10A (MIRN10A; 610173) and miR10B (MIRN10B; 611576) showed the greatest upregulation, with increases of 20- and 16.67-fold, respectively. Mir22 (MIRN22; 612077) showed greatest downregulation, with a reduction of 0.31-fold. Garzon et al. (2008) concluded that AML with NPM1 mutations has a distinctive miRNA signature.
The Cancer Genome Atlas Research Network (2013) analyzed the genomes of 200 clinically annotated adult cases of de novo AML, using either whole-genome sequencing (50 cases) or whole-exome sequencing (150 cases), along with RNA and microRNA sequencing and DNA methylation analysis. The authors identified recurrent mutations in the NPM1 gene in 54 of 200 (27%) samples.
Brewin et al. (2013) noted that the study of the Cancer Genome Atlas Research Network (2013) did not reveal which mutations occurred in the founding clone, as would be expected for an initiator of disease, and which occurred in minor clones, which subsequently drive disease. Miller et al. (2013) responded that genes mutated almost exclusively in founding clones in their study included NPM1 (3 of 3 mutations in founding clones). They identified several other genes that contained mutations they considered probable initiators, and other genes in which mutations were considered probably cooperating mutations.
Ivey et al. (2016) used quantitative RT-PCR assays to detect minimal residual disease in 2,569 samples obtained from 346 patients with NPM1-mutated AML who had undergone intensive treatment in the National Cancer Research Institute AML17 trial. The authors used a custom 51-gene panel to perform targeted sequencing of 223 samples obtained at the time of diagnosis and 49 samples obtained at the time of relapse. Mutations associated with preleukemic clones were tracked by means of digital polymerase chain reaction. Molecular profiling highlighted the complexity of NPM1-mutated AML, with segregation of patients into more than 150 subgroups, thus precluding reliable outcome prediction. The determination of minimal residual disease status was more informative. Persistence of NPM1-mutated transcripts in blood was present in 15% of the patients after the second chemotherapy cycle and was associated with a greater risk of relapse after 3 years of follow-up than was an absence of such transcripts (82% vs 30%; hazard ratio 4.80; 95% CI 2.95-7.80; p less than 0.001) and a lower rate of survival (24% vs 75%; hazard ratio for death, 4.38; 95% CI 2.57-7.47; p less than 0.001). The presence of minimal residual disease was the only independent prognostic factor for death in multivariate analysis (hazard ratio, 4.84; 95% CI 2.57 to 9.15; p less than 0.001). These results were validated in an independent cohort. On sequential monitoring of minimal residual disease, relapse was reliably predicted by a rising level of NPM1-mutated transcripts. Although mutations associated with preleukemic clones remained detectable during ongoing remission after chemotherapy, NPM1 mutations were detected in 69 of 70 patients at the time of relapse and provided a better marker of disease status.
Associations Pending Confirmation
For discussion of a possible association between dyskeratosis congenita (see, e.g., DKCA1, 127550) and germline variation in the NPM1 gene, see 164040.0005 and 164040.0006. Also see ANIMAL MODEL.
Gale et al. (2008) found that 354 (26%) of 1,425 patients with AML had the FLT3 internal duplication. The median total mutant level for all patients was 35% of total FLT3, but there was wide variation with levels ranging from 1 to 96%. There was a significant correlation between worse overall survival, relapse risk, and increased white blood cell count with increased mutant level, but the size of the duplication and the number of mutations had no significant impact on outcome. Those patients with the FLT3 duplication had a worse risk of relapse than patients without the FLT3 duplication. Among a subset of 1,217 patients, 503 (41%) had a mutation in the NPM1 gene (164040), and 208 (17%) had mutations in both genes. The presence of an NPM1 mutation had a beneficial effect on the remission rate, most likely due to a lower rate of resistant disease, both in patients with and without FLT3 duplications. Gale et al. (2008) identified 3 prognostic groups among AML patients: good in those with only a NPM1 mutation; intermediate in those with either no FLT3 or NPM1 mutations or mutations in both genes; and poor in those with only FLT3 mutations.
Cheng et al. (1999) generated transgenic mice with Plzf-Rara and Npm-Rara. Plzf-Rara transgenic animals developed chronic myeloid leukemia-like phenotypes at an early stage in life (within 3 months in 5 of 6 mice), whereas 3 Npm-Rara transgenic mice showed a spectrum of phenotypes from typical APL to chronic myeloid leukemia relatively late in life (from 12 to 15 months). In contrast to bone marrow cells from Plzf-Rara transgenic mice, those from Npm-Rara transgenic mice could be induced to differentiate by all-trans-retinoic acid (ATRA). Cheng et al. (1999) found that in interacting with nuclear coreceptors the 2 fusion proteins had different ligand sensitivities, which may be the underlying molecular mechanism for differential responses to ATRA. These data clearly established the leukemogenic role of PLZF-RARA and NPM-RARA and the importance of fusion receptor/corepressor interactions in the pathogenesis as well as in determining different clinical phenotypes of APL.
To study the function of Npm in vivo, Grisendi et al. (2005) generated a hypomorphic Npm1 mutant series comprising Npm1 heterozygous-null, hypomorphic mutant, and homozygous-null mice. They observed that Npm1 homozygous-null and hypomorphic mutants had aberrant organogenesis and died between embryonic days 11.5 and 16.5 owing to severe anemia resulting from defects in primitive hematopoiesis. Grisendi et al. (2005) showed that Npm1 inactivation leads to unrestricted centrosome duplication and genomic instability. Grisendi et al. (2005) demonstrated that Npm is haploinsufficient in the control of genetic stability and that Npm1 heterozygosity accelerates oncogenesis both in vitro and in vivo. Notably, Npm1 heterozygous mice developed a hematologic syndrome with features of human myelodysplastic syndrome (MDS). Grisendi et al. (2005) concluded that their data uncovered an essential developmental role for Npm and implicated its functional loss in tumorigenesis and MDS pathogenesis.
Nachmani et al. (2019) found that mice with hematopoietic-specific knockout of Npm1 exhibited dysmegakaryopoiesis, defective erythroid maturation, dysplastic and low platelet counts, and dysplastic neutrophils, leading to bone marrow failure (BMF). Mice with knockin of the human NPM1 asp180 deletion mutation (D180del) associated with dyskeratosis congenita (see 127550) were born in mendelian ratios with no overt developmental or behavioral abnormalities. However, as the mice aged, hematopoietic stem cells of both heterozygous and homozygous knockin mice underwent exhaustion due to the defective 2-prime-O-methylation, resulting in BMF. Both heterozygous and homozygous knockin mice also recapitulated the multiorgan features of human dyskeratosis congenita.
In Npm1C/Dnmt3a (602769) mutant knockin mice, a model of AML development, leukemia is preceded by a period of extended myeloid progenitor cell proliferation and self-renewal. Uckelmann et al. (2020) found that this self-renewal can be reversed by oral administration of a small molecule that targets the MLL1-Menin (159555/613733) chromatin complex. Uckelmann et al. (2020) suggested that their preclinical results supported the hypothesis that individuals at high risk of developing AML might benefit from targeted epigenetic therapy in a preventative setting.
In 40 of 51 cases of acute myeloid leukemia (601626) with positivity for NPM in the cytoplasm, Falini et al. (2005) identified a 4-bp duplication in exon 12 of the NPM1 gene (956dupTCTG), resulting in a shift in the reading frame that was predicted to alter the C-terminal portion of the protein by replacing the last 7 amino acids with 11 different residues. Falini et al. (2005) called this mutation, which was the most frequent of those identified, mutation A.
In 7 of 51 cases of acute myeloid leukemia (601626) with positivity for NPM in the cytoplasm, Falini et al. (2005) identified a 4-bp insertion in exon 12 of the NPM1 gene (960insCATG), resulting in a shift in the reading frame that was predicted to alter the C-terminal portion of the protein by replacing the last 7 amino acids with 11 different residues. Falini et al. (2005) called this mutation B.
In 1 of 51 cases of acute myeloid leukemia (601626) with positivity for NPM in the cytoplasm, Falini et al. (2005) identified a 4-bp insertion in exon 12 of the NPM1 gene (960insCGTG), resulting in a shift in the reading frame that was predicted to alter the C-terminal portion of the protein by replacing the last 7 amino acids with 11 different residues. Falini et al. (2005) called this mutation C.
In 1 of 51 cases of acute myeloid leukemia (601626) with positivity for NPM in the cytoplasm, Falini et al. (2005) identified a 4-bp insertion in exon 12 of the NPM1 gene (960insCCTG), resulting in a shift in the reading frame that was predicted to alter the C-terminal portion of the protein by replacing the last 7 amino acids with 11 different residues. Falini et al. (2005) called this mutation D.
This variant is classified as a variant of unknown significance because its contribution to dyskeratosis congenita (see, e.g., DKCA1, 127550) has not been confirmed.
In a patient (CM108) who presented at birth with features of dyskeratosis congenita, Nachmani et al. (2019) identified a germline, presumably heterozygous c.532G-C transversion (c.532G-C, NM_001355006.1) in the NPM1 gene, resulting in an asp178-to-his (D178H) substitution within an acidic D/E repeat region that regulates the specificity of NPM1 binding to RNA. In vitro studies showed that the variant NPM1 protein had impaired capacity to bind various snoRNAs compared to controls. Detailed analysis of fibroblasts derived from the patient showed impaired binding of fibrillarin (FBL) to NPM1-bound snoRNAs. Patient cells showed decreased 2-prime-O Me of 28S rRNA, a reduction in IRES-dependent activity, and evidence of translational dysregulation compared to controls, although global translation and nucleolar localization were preserved. The variant was not able to rescue the defects in NPM1-depleted cells, suggesting a loss of function. The patient had severe growth defects, thumb abnormalities, and thrombocytopenia. The mutation was found by a review of whole-exome sequence datasets from patients with DKC; the NPM1 gene was chosen for analysis because of its function. Zygosity of the variant and familial segregation information was not provided.
This variant is classified as a variant of unknown significance because its contribution to dyskeratosis congenita (see, e.g., DKCA1, 127550) has not been confirmed.
In a patient with features of dyskeratosis congenita, Nachmani et al. (2019) identified a germline presumably heterozygous 3-bp deletion in the NPM1 gene (c.538_540del, NM_001355006.1), resulting in an in-frame deletion (Asp180del) within an acidic D/E repeat region that regulates the specificity of NPM1 binding to RNA. In vitro studies showed that the variant NPM1 protein had impaired capacity to bind various snoRNAs compared to controls. Studies of mouse embryonic fibroblasts engineered to carry the D180del mutation showed impaired 2-prime-O Me compared to controls. The variant was not able to rescue the defects in NPM1-depleted cells, suggesting a loss of function. The patient presented with skin pigmentation abnormalities, nail dystrophy, microcephaly, developmental delay, short stature, and radial skeletal anomalies, and developed bone marrow failure (BMF) by age 6 years. The mutation was found by a review of whole-exome sequence datasets from patients with DKC; the NPM1 gene was chosen for analysis because of its function. Zygosity of the variant and familial segregation information was not provided. Nachmani et al. (2019) found that mice with knockin of the human NPM1 D180del mutation were born in mendelian ratios with no overt developmental or behavioral abnormalities. However, as the mice aged, hematopoietic stem cells of both heterozygous and homozygous knockin mice underwent exhaustion due to the defective 2-prime-O-methylation, resulting in BMF. Both heterozygous and homozygous knockin mice also recapitulated the multiorgan features of human dyskeratosis congenita.
Brewin, J., Horne, G., Chevassut, T. Genomic landscapes and clonality of de novo AML. (Letter) New Eng. J. Med. 369: 1472-1473, 2013. [PubMed: 24106951] [Full Text: https://doi.org/10.1056/NEJMc1308782]
Cancer Genome Atlas Research Network. Genomic and epigenomic landscapes of adult de novo acute myeloid leukemia. New Eng. J. Med. 368: 2059-2074, 2013. Note: Erratum: New Eng. J. Med. 369: 98 only, 2013. [PubMed: 23634996] [Full Text: https://doi.org/10.1056/NEJMoa1301689]
Chan, W.-Y., Liu, Q.-R., Borjigin, J., Busch, H., Rennert, O. M., Tease, L. A., Chan, P.-K. Characterization of the cDNA encoding human nucleophosmin and studies of its role in normal and abnormal growth. Biochemistry 28: 1033-1039, 1989. [PubMed: 2713355] [Full Text: https://doi.org/10.1021/bi00429a017]
Cheng, G.-X., Zhu, X.-H., Men, X.-Q., Wang, L., Huang, Q.-H., Jin, X. L., Xiong, S.-M., Zhu, J., Guo, W.-M., Chen, J.-Q., Xu, S.-F., So, E., Chan, L.-C., Waxman, S., Zelent, A., Chen, G.-Q., Dong, S., Liu, J.-X., Chen, S.-J. Distinct leukemia phenotypes in transgenic mice and different corepressor interactions generated by promyelocytic leukemia variant fusion genes PLZF-RAR-alpha and NPM-RAR-alpha. Proc. Nat. Acad. Sci. 96: 6318-6323, 1999. [PubMed: 10339585] [Full Text: https://doi.org/10.1073/pnas.96.11.6318]
Dalenc, F., Drouet, J., Ader, I., Delmas, C., Rochaix, P., Favre, G., Cohen-Jonathan, E., Toulas, C. Increased expression of a COOH-truncated nucleophosmin resulting from alternative splicing is associated with cellular resistance to ionizing radiation in HeLa cells. Int. J. Cancer 100: 662-668, 2002. [PubMed: 12209603] [Full Text: https://doi.org/10.1002/ijc.10558]
Dutta, S., Akey, I. V., Dingwall, C., Hartman, K. L., Laue, T., Nolte, R. T., Head, J. F., Akey, C. W. The crystal structure of nucleoplasmin-core: implications for histone binding and nucleosome assembly. Molec. Cell 8: 841-853, 2001. [PubMed: 11684019] [Full Text: https://doi.org/10.1016/s1097-2765(01)00354-9]
Falini, B., Mecucci, C., Tiacci, E., Alcalay, M., Rosati, R., Pasqualucci, L., La Starza, R., Diverio, D., Colombo, E., Santucci, A., Bigerna, B., Pacini, R., and 11 others. Cytoplasmic nucleophosmin in acute myelogenous leukemia with a normal karyotype. New Eng. J. Med. 352: 254-266, 2005. Note: Erratum: New Eng. J. Med. 352: 740 only, 2005. [PubMed: 15659725] [Full Text: https://doi.org/10.1056/NEJMoa041974]
Fukawa, T., Ono, M., Matsuo, T., Uehara, H., Miki, T., Nakamura, Y., Kanayama, H., Katagiri, T. DDX31 regulates the p53-HDM2 pathway and rRNA gene transcription through its interaction with NPM1 in renal cell carcinomas. Cancer Res. 72: 5867-5877, 2012. [PubMed: 23019224] [Full Text: https://doi.org/10.1158/0008-5472.CAN-12-1645]
Gale, R. E., Green, C., Allen, C., Mead, A. J., Burnett, A. K., Hills, R. K., Linch, D. C. The impact of FLT3 tandem duplication mutant level, number, size, and interaction with NPM1 mutations in a large cohort of young adult patients with acute myeloid leukemia. Blood 111: 2776-2784, 2008. [PubMed: 17957027] [Full Text: https://doi.org/10.1182/blood-2007-08-109090]
Garzon, R., Garofalo, M., Martelli, M. P., Briesewitz, R., Wang, L., Fernandez-Cymering, C., Volinia, S., Liu, C.-G., Schnittger, S., Haferlach, T., Liso, A., Diverio, D., Mancini, M., Meloni, G., Foa, R., Martelli, M. F., Mecucci, C., Croce, C. M., Falini, B. Distinctive microRNA signature of acute myeloid leukemia bearing cytoplasmic mutated nucleophosmin. Proc. Nat. Acad. Sci. 105: 3945-3950, 2008. [PubMed: 18308931] [Full Text: https://doi.org/10.1073/pnas.0800135105]
Grisendi, S., Bernardi, R., Rossi, M., Cheng, K., Khandker, L., Manova, K., Pandolfi, P. P. Role of nucleophosmin in embryonic development and tumorigenesis. Nature 437: 147-153, 2005. [PubMed: 16007073] [Full Text: https://doi.org/10.1038/nature03915]
Grisendi, S., Pandolfi, P. P. NPM mutations in acute myelogenous leukemia. (Editorial) New Eng. J. Med. 352: 291-292, 2005. [PubMed: 15659732] [Full Text: https://doi.org/10.1056/NEJMe048337]
Gross, M. B. Personal Communication. Baltimore, Md. 11/20/2019.
Ivey, A., Hills, R. K., Simpson, M. A., Jovanovic, J. V., Gilkes, A., Grech, A., Patel, Y., Bhudia, N., Farah, H., Mason, J., Wall, K., Akiki, S., and 10 others. Assessment of minimal residual disease in standard-risk AML. New Eng. J. Med. 374: 422-433, 2016. [PubMed: 26789727] [Full Text: https://doi.org/10.1056/NEJMoa1507471]
Miller, C. A., Wilson, R. K., Ley, T. J. Reply to Brewin et al. (Letter) New Eng. J. Med. 369: 1473 only, 2013. [PubMed: 24106950] [Full Text: https://doi.org/10.1056/NEJMc1308782]
Morris, S. W., Kirstein, M. N., Valentine, M. B., Dittmer, K. G., Shapiro, D. N., Saltman, D. L., Look, A. T. Fusion of a kinase gene, ALK, to a nucleolar protein gene, NPM, in non-Hodgkin's lymphoma. Science 263: 1281-1284, 1994. Note: Erratum: Science 267: 316-317, 1995. [PubMed: 8122112] [Full Text: https://doi.org/10.1126/science.8122112]
Nachmani, D., Bothmer, A. H., Grisendi, S., Mele, A., Bothmer, D., Lee, J. D., Monteleone, E., Cheng, K., Zhang, Y., Bester, A. C., Guzzetti, A., Mitchell, C. A., and 16 others. Germline NPM1 mutations lead to altered rRNA 2-prime-O-methylation and cause dyskeratosis congenita. Nature Genet. 51: 1518-1529, 2019. [PubMed: 31570891] [Full Text: https://doi.org/10.1038/s41588-019-0502-z]
Okuda, M., Horn, H. F., Tarapore, P., Tokuyama, Y., Smulian, A. G., Chan, P.-K., Knudsen, E. S., Hofmann, I. A., Snyder, J. D., Bove, K. E., Fukasawa, K. Nucleophosmin/B23 is a target of CDK2/cyclin E in centrosome duplication. Cell 103: 127-140, 2000. [PubMed: 11051553] [Full Text: https://doi.org/10.1016/s0092-8674(00)00093-3]
Redner, R. L., Rush, E. A., Faas, S., Rudert, W. A., Corey, S. J. The t(5;17) variant of acute promyelocytic leukemia expresses a nucleophosmin-retinoic acid receptor fusion. Blood 87: 882-886, 1996. [PubMed: 8562957]
Uckelmann, H. J., Kim, S. M., Wong, E. M., Hatton, C., Giovinazzo, H., Gadrey, J. Y., Krivtsov, A. V., Rucker, F. G., Dohner, K., McGeehan, G. M., Levine, R. L., Bullinger, L., Vassiliou, G. S., Armstrong, S. A. Therapeutic targeting of preleukemia cells in a mouse model of NPM1 mutant acute myeloid leukemia. Science 367: 586-590, 2020. [PubMed: 32001657] [Full Text: https://doi.org/10.1126/science.aax5863]
Zhang, Q., Wang, H. Y., Liu, X., Wasik, M. A. STAT5A is epigenetically silenced by the tyrosine kinase NPM1-ALK and acts as a tumor suppressor by reciprocally inhibiting NPM1-ALK expression. Nature Med. 13: 1341-1348, 2007. [PubMed: 17922009] [Full Text: https://doi.org/10.1038/nm1659]