Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0023418 (leukemia)
 93,477 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Since the first report about cytoplasmic nucleophosmin (NPM) in acute myelogenous leukemia with a normal karyotype was announced, the shuttling activity of NPM and its proper subcellular localization have drawn many attentions. Mechanisms that regulate nucleocytoplasmic transport of proteins may provide novel opportunities for drug development. Here we show that, in Jurkat cells, strong fluorescence density of NPM prevails in the nucleus, while, some key nucleoporins: Nup88 and Nup214 localize mainly in the cytoplasm. Deguelin, a natural occurring rotenoid, presents powerful anti-leukemia effects through proliferation inhibition and apoptosis induction in Jurkat cells. Deguelin downregulates the expression of NPM, Nup88 and Nup214 in a dose-dependent manner and reverts the localization of Nup88 and Nup214 to nuclear rim. These results suggest that deguelin exhibit its strong anti-leukemia effects might through the regulation of some nucleoporins, thus influence the subsequent abnormal expressions or localizations of some key proteins involved in proliferation and/or apoptosis, such as: NPM.
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PMID:Deguelin represses both the expression of nucleophosmin and some nucleoporins: Nup88 and Nup214 in Jurkat cells. 1817 37

Frameshift mutations of the nucleophosmin gene (NPM1) were recently reported as a frequently occurring abnormality in patients with de novo acute myeloid leukemia (AML). To evaluate the frequency of NPM1 mutations in patients with therapy-related myelodysplasia (t-MDS) and therapy-related AML (t-AML), and their possible association to type of previous therapy and to other gene mutations, 140 patients with t-MDS or t-AML were analyzed for mutations of NPM1. NPM1 mutations were observed in 7 of 51 patients presenting as overt t-AML, as compared to only 3 of 89 patients presenting as t-MDS (P=0.037). The mutations were not related to any specific type of previous therapy, but they were significantly associated with a normal karyotype and mutations of FLT3 (P=0.0002 for both comparisons). Only 1 of 10 patients with NPM1 mutations presented chromosome aberrations characteristic of therapy-related disease, and 7q-/-7, the most frequent abnormalities of t-MDS/t-AML, were not observed (P=0.002). This raises the question whether some of the cases presenting NPM1 mutations were in fact cases of de novo leukemia. The close association to class I mutations and the inverse association to class II mutations suggest mutations of NPM1 as representing a class II mutation-like abnormality in AML.
Leukemia 2008 May
PMID:NPM1 mutations in therapy-related acute myeloid leukemia with uncharacteristic features. 1827 44

Acute myeloid leukemia (AML) carrying NPM1 mutations and cytoplasmic nucleophosmin (NPMc+ AML) accounts for about one-third of adult AML and shows distinct features, including a unique gene expression profile. MicroRNAs (miRNAs) are small noncoding RNAs of 19-25 nucleotides in length that have been linked to the development of cancer. Here, we investigated the role of miRNAs in the biology of NPMc+ AML. The miRNA expression was evaluated in 85 adult de novo AML patients characterized for subcellular localization/mutation status of NPM1 and FLT3 mutations using a custom microarray platform. Data were analyzed by using univariate t test within BRB tools. We identified a strong miRNA signature that distinguishes NPMc+ mutated (n = 55) from the cytoplasmic-negative (NPM1 unmutated) cases (n = 30) and includes the up-regulation of miR-10a, miR-10b, several let-7 and miR-29 family members. Many of the down-regulated miRNAs including miR-204 and miR-128a are predicted to target several HOX genes. Indeed, we confirmed that miR-204 targets HOXA10 and MEIS1, suggesting that the HOX up-regulation observed in NPMc+ AML may be due in part by loss of HOX regulators-miRNAs. FLT3-ITD+ samples were characterized by up-regulation of miR-155. Further experiments demonstrated that the up-regulation of miR-155 was independent from FLT3 signaling. Our results identify a unique miRNA signature associated with NPMc+ AML and provide evidence that support a role for miRNAs in the regulation of HOX genes in this leukemia subtype. Moreover, we found that miR-155 was strongly but independently associated with FLT3-ITD mutations.
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PMID:Distinctive microRNA signature of acute myeloid leukemia bearing cytoplasmic mutated nucleophosmin. 1830 31

Almost half of adult acute myelogenous leukemia (AML) is normal cytogenetically, and this subgroup shows a remarkable heterogeneity of genetic mutations at the molecular level and an intermediate response to therapy. The finding of recurrent cytogenetic abnormalities has influenced, in a primary way, the understanding and treatment of leukemias. Yet "normal karyotype AML" lacks such obvious abnormalities, but has a variety of prognostically important genetic abnormalities. Thus, the presence of a FLT3-ITD (internal tandem duplication), MLL-PTD (partial tandem duplication), or the increased expression of ERG or EVI1 mRNAs confer a poor prognosis, and an increased risk of relapse. In contrast, the presence of cytoplasmic nucleophosmin or C/EBPA mutations is associated with lower relapse rates and improved survival. Although resistance to treatment is associated with specific mutations, the degree to which the leukemia resembles a stem cell in its functional properties may provide greater protection from the effects of treatment. Although usually all of the circulating leukemia cells are cleared following treatment, a small residual population of leukemic cells in the bone marrow persists, making this disease hard to eradicate. Increased understanding of the biological consequences of at least some of these mutations in "normal karyotype AML" is leading to more targeted approaches to develop more effective treatments for this disease.
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PMID:Is it important to decipher the heterogeneity of "normal karyotype AML"? 1834 11

Mutations in nucleophosmin (NPM) exon 12 and the resulting delocalization of NPM into the cytoplasm are the most specific and frequent cellular events in acute myeloid leukemia patients (AML) with normal karyotype. Cytoplasmatic NPM (NPMc+) is associated with responsiveness to chemotherapy and better prognosis. The activation of nuclear factor-kappaB (NF-kappaB) has been demonstrated to occur in a subset of AML patients and is thought to induce resistance to many chemotherapeutical agents. In this study, we demonstrate the increased in vitro sensitivity of NPMc+ cells to chemotherapeutical agents and their reduced NF-kappaB activity. Furthermore, we provide evidence of the interaction between NPMc+ and NF-kappaB in the cytoplasm, resulting in the sequestration and inactivation of NF-kappaB. The cytosolic localization and consequent inactivation of NF-kappaB justifies the reduced NF-kappaB DNA-binding activity observed in NPMc+ patients. These data, taken together, may provide a possible explanation for the increased rate of chemosensitivity observed among the NPMc+ patients.
Leukemia 2008 Jun
PMID:Increase sensitivity to chemotherapeutical agents and cytoplasmatic interaction between NPM leukemic mutant and NF-kappaB in AML carrying NPM1 mutations. 2037 85

Mutations affecting NPM1 (nucleophosmin) are the most common genetic lesions found in acute myeloid leukemia (AML). NPM1 is one of the most abundant proteins found in the nucleolus and has links to the MDM2/p53 tumor suppressor pathway. A distinctive feature of NPM1 mutants in AML is their aberrant localization to the cytoplasm of leukemic cells. This mutant phenotype is the result of the substitution of several C-terminal residues, including one or two conserved tryptophan residues, with a leucine-rich nuclear export signal. The exact molecular mechanism underlying the loss of nucleolar retention, and the role of the tryptophans, remains unknown. In this study we have determined the structure of an independently folded globular domain in the C terminus of NPM1 using NMR spectroscopy, and we report that the conserved tryptophans are critical for structure. This domain is necessary for the nucleolar targeting of NPM1 and is disrupted by mutations in AML with cytoplasmic NPM1. Furthermore, we identify conserved surface-exposed lysine residues that are functionally rather than structurally important for nucleolar localization. This study provides new focus for efforts to understand the pathogenesis of AML with cytoplasmic NPM1 and may be used to aid the design of small molecules that target the C-terminal domain of NPM1 to act as novel anti-proliferative and anti-leukemia therapeutics.
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PMID:Structural consequences of nucleophosmin mutations in acute myeloid leukemia. 1851 15

Acute myeloid leukemia with mutated NPM1 gene and aberrant cytoplasmic expression of nucleophosmin (NPMc(+) acute myeloid leukemia) shows distinctive biological and clinical features. Experimental evidence of the oncogenic potential of the nucleophosmin mutant is, however, still lacking, and it is unclear whether other genetic lesion(s), e.g. FLT3 internal tandem duplication, cooperate with NPM1 mutations in acute myeloid leukemia development. An analysis of age-specific incidence, together with mathematical modeling of acute myeloid leukemia epidemiology, can help to uncover the number of genetic events needed to cause leukemia. We collected data on age at diagnosis of acute myeloid leukemia patients from five European Centers in Germany, The Netherlands and Italy, and determined the age-specific incidence of AML with mutated NPM1 (a total of 1,444 cases) for each country. Linear regression of the curves representing age-specific rates of diagnosis per year showed similar slopes of about 4 on a double logarithmic scale. We then adapted a previously designed mathematical model of hematopoietic tumorigenesis to analyze the age incidence of acute myeloid leukemia with mutated NPM1 and found that a one-mutation model can explain the incidence curve of this leukemia entity. This model fits with the hypothesis that NPMc(+) acute myeloid leukemia arises from an NPM1 mutation with haploinsufficiency of the wild-type NPM1 allele.
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PMID:A one-mutation mathematical model can explain the age incidence of acute myeloid leukemia with mutated nucleophosmin (NPM1). 1860 63

Deregulated HOX expression, by chromosomal translocations and myeloid-lymphoid leukemia (MLL) rearrangements, is causal in some types of leukemia. Using real-time reverse transcription-PCR, we examined the expression of 43 clustered HOX, polycomb, MLL and FLT3 genes in 119 newly diagnosed adult acute myeloid leukemias (AMLs) selected from all major cytogenetic groups. Downregulated HOX expression was a consistent feature of favorable AMLs and, among these cases, inv(16) cases had a distinct expression profile. Using a 17-gene predictor in 44 additional samples, we observed a 94.7% specificity for classifying favorable vs intermediate/unfavorable cytogenetic groups. Among other AMLs, HOX overexpression was associated with nucleophosmin (NPM) mutations and we also identified a phenotypically similar subset with wt-NPM. In many unfavorable and other intermediate cytogenetic AMLs, HOX levels resembled those in normal CD34+ cells, except that the homogeneity characteristic of normal samples was not present. We also observed that HOXA9 levels were significantly inversely correlated with survival and that BMI-1 was overexpressed in cases with 11q23 rearrangements, suggesting that p19(ARF) suppression may be involved in MLL-associated leukemia. These results underscore the close relationship between HOX expression patterns and certain forms of AML and emphasize the need to determine whether these differences play a role in the disease process.
Leukemia 2008 Nov
PMID:HOX expression patterns identify a common signature for favorable AML. 1866 34

The anaplastic lymphoma kinase (ALK) is an oncogene product involved in hematopoietic and non-hematopoietic malignancies. Recent studies have demonstrated that nucleophosmin (NPM)-ALK, originated from the fusion of NPM and ALK genes, causes cell transformation through diverse mechanisms. Here, we show a novel mechanism by which NPM-ALK transforms lymphoid tumor cells to become resistant to glucocorticoid (GC) or dexamethasone (Dex) treatment. Transformed BaF3 cells by NPM-ALK were much more resistant to Dex compared with their parental cells, and concurrently had a constitutive activation of mammalian target of rapamycin (mTOR) signaling, as evidenced by hyperphosphorylation of its downstream effectors, p70 S6 kinase (p70S6K) and eukaryotic initiation factor 4E-binding protein 1 (4E-BP1). The mTOR inhibitor rapamycin suppressed activation of p70S6K in BaF3/NPM-ALK cells and reversed GC resistance by synergistically inhibiting mTOR signaling pathway, enhancing cell cycle arrest at G(1) phase and promoting apoptotic cell death. In conclusion, our data indicate that the ALK fusion kinase, NPM-ALK, induces GC resistance by activating mTOR signaling, and addition of mTOR inhibitors to the chemotherapeutic regimen of ALK+ lymphomas may improve the prognosis.
Leukemia 2008 Nov
PMID:Rapamycin reverses NPM-ALK-induced glucocorticoid resistance in lymphoid tumor cells by inhibiting mTOR signaling pathway, enhancing G1 cell cycle arrest and apoptosis. 1868 9

This study was aimed to establish the PCR methods to detect nucleophosmin (NPM) gene and its mutation. 2 leukemia cell lines and 23 specimens from patients with acute myelogenous leukemia (AML) were investigated. The level of NPM mRNA was detected by RT-PCR. The exon-12 of NPM gene in leukemia cell lines was amplified by PCR and sequenced. Using the plasmid containing cDNA of NPM mutation A as a positive template, the PCR procedure to detect mutation A was established and evaluated. Then, the mutation of NPM was analyzed in 23 AML specimens. The results indicated that the expression level of NPM in leukemia cell lines was higher than that in normal cells. Different overexpression levels of NPM mRNA were found in all 23 AML specimens. PCR indicated that mutation had been not occurred at NPM exon-12 in THP1 and K562 cells, but a T base was deleted at 3' untranslated region of NPM gene in K562 cells. The PCR used for directly detecting NPM mutation A can specially amplify the NPM mutation gene. The method was reproducible, whose coefficient of variability was 1.6% and 3.1% in intra-and inter-assays respectively. The lowest detectable limit was 100 pg cDNA. Using the PCR methods, NPM mutation A could be detected in 2 out of 23 AML specimens, but NPM mutation A was not found in THP1 and K562 cells. It is concluded that the RT-PCT method detecting NPM mRNA level and the PCR method detecting directly NPM mutation are established. NPM mRNA is overexpressed in leukemia cells; NPM mutation A occurs in some AML patients.
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PMID:[Establishment of the methods to detect nucleophosmin gene and its mutation in acute myelogenous leukemia]. 1871 53


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