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https://www.readbyqxmd.com/read/27906185/anti-proliferative-activity-of-the-npm1-interacting-natural-product-avrainvillamide-in-acute-myeloid-leukemia
#1
Vibeke Andresen, Bjarte S Erikstein, Herschel Mukherjee, André Sulen, Mihaela Popa, Steinar Sørnes, Håkon Reikvam, Kok-Ping Chan, Randi Hovland, Emmet McCormack, Øystein Bruserud, Andrew G Myers, Bjørn T Gjertsen
Mutated nucleophosmin 1 (NPM1) acts as a proto-oncogene and is present in ~30% of patients with acute myeloid leukemia (AML). Here we examined the in vitro and in vivo anti-leukemic activity of the NPM1 and chromosome region maintenance 1 homolog (CRM1) interacting natural product avrainvillamide (AVA) and a fully syntetic AVA analog. The NPM1-mutated cell line OCI-AML3 and normal karyotype primary AML cells with NPM1 mutations were significantly more sensitive towards AVA than cells expressing wild-type (wt) NPM1...
December 1, 2016: Cell Death & Disease
https://www.readbyqxmd.com/read/27899775/-leukemia
#2
Minenori Eguchi-Ishimae, Mariko Eguchi
Leukemia is derived from hematopoietic stem/progenitor cells that have acquired genetic abnormalities, leading to malignant transformation. The basis of therapyfor leukemia is a combination of anti-cancer drugs based on risk stratification. The overall 5-year survival rate in leukemia patients of all ages is still 40%, although it has improved in pediatric patients. Leuke- mia itself is a heterogeneous disease that includes various entities/subtypes with different pathogenic gene aberrations. Selection of the treatment strategylargelydepends on risk stratification, and this in turn is mainlybased on specific recurrent chromosome aberrations...
November 2016: Gan to Kagaku Ryoho. Cancer & Chemotherapy
https://www.readbyqxmd.com/read/27865970/insights-into-amyloid-like-aggregation-of-h2-region-of-the-c-terminal-domain-of-nucleophosmin
#3
Anna Russo, Carlo Diaferia, Sara La Manna, Cinzia Giannini, Teresa Sibillano, Antonella Accardo, Giancarlo Morelli, Ettore Novellino, Daniela Marasco
Nucleophosmin (NPM1) is a multifunctional protein involved in a variety of biological processes including the pathogenesis of several human malignancies and is the most frequently mutated gene in Acute Myeloid Leukemia (AML). To deepen the role of protein regions in its biological activities, lately we reported on the structural behavior of dissected C-terminal domain (CTD) helical fragments. Unexpectedly the H2 (residues 264-277) and H3 AML-mutated regions showed a remarkable tendency to form amyloid-like assemblies with fibrillar morphology and β-sheet structure that resulted as toxic when exposed to human neuroblastoma cells...
November 17, 2016: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/27864740/expression-levels-of-warburg-effect-related-micrornas-correlate-with-each-other-and-that-of-histone-deacetylase-enzymes-in-adult-hematological-malignancies-with-emphasis-on-acute-myeloid-leukemia
#4
Zsuzsanna Gaál, Éva Oláh, László Rejtő, Bálint László Bálint, László Csernoch
Disruption of epigenetic regulation and characteristic metabolic alterations (known as the Warburg-effect) are well-known hallmarks of cancer. In our study we investigated the expression levels of microRNAs and histone deacetylase enzymes via RT-qPCR in bone marrow specimens of adult patients suffering from hematological malignancies (total cohort n = 40), especially acute myeloid leukemia (n = 27). The levels of the three examined Warburg-effect related microRNAs (miR-378*, miR-23b, miR-26a) positively correlated with each other and the oncogenic miR-155 and miR-125b, while negatively with the level of the tumorsuppressor miR-124...
November 18, 2016: Pathology Oncology Research: POR
https://www.readbyqxmd.com/read/27835920/-acute-myeloid-leukemia
#5
Jan Braess
Acute myeloid leukemia (AML) has been genetically characterized extensively and can now be subdivided into 9 to 11 pathogenetically different subtypes according to their profile of driver mutations. In clinical practice karyotyping and molecular analysis of NPM1, cEBPa and FLT3-ITD are required for treatment stratification and potentially genotype specific treatment. Some markers such as NPM1 not only offer prognostic information but can also serve as markers of minimal residual disease and thus have the potential to guide therapy in the future...
November 2016: Deutsche Medizinische Wochenschrift
https://www.readbyqxmd.com/read/27798920/pre-transplant-quantitative-determination-of-npm1-mutation-significantly-predicts-outcome-of-ailogeneic-hematopoietic-stem-cell-transplantation-in-patients-with-normal-karyotype-aml-in-complete-remission
#6
Michal Karas, Katerina Steinerova, Daniel Lysak, Marcela Hrabetova, Alexandra Jungova, Jiri Sramek, Pavel Jindra, Jiri Polivka, Lubos Holubec
BACKGROUND/AIM: Minimal residual disease (MRD) in patients with acute myeloid leukemia (AML) before allogeneic hematopoietic stem cell transplantation (alloHSCT) can influence the results of therapy. With the aim of evaluating the potential role of pre-transplant MRD, we studied the impact of pre-transplant MRD level on the outcome of alloHSCT in patients with AML in complete remission (CR). PATIENTS AND METHODS: From 2/2005 to 9/2014, 60 patients with a median age of 54 years (range=30-66 years) with normal karyotype-AML harboring nucleophosmin 1 (NPM1) mutation [53% Fms-related tyrosine kinase receptor 3 internal tandem duplication (FLT3/ITD)-positive] in first (n=45) or second (n=15) CR underwent myeloablative (n=16) or reduced-intensity (n=44) alloHSCT (27% related, 73% unrelated)...
October 2016: Anticancer Research
https://www.readbyqxmd.com/read/27784745/mutational-landscape-and-gene-expression-patterns-in-adult-acute-myeloid-leukemias-with-monosomy-7-as-a-sole-abnormality
#7
Ann-Kathrin Eisfeld, Jessica Kohlschmidt, Krzysztof Mrozek, Stefano Volinia, James S Blachly, Deedra Nicolet, Christopher Oakes, Karl Kroll, Shelley Orwick, Andrew J Carroll, Richard M Stone, John C Byrd, Albert de la Chapelle, Clara D Bloomfield
Monosomy of chromosome 7 is the most frequent autosomal monosomy in acute myeloid leukemia (AML), where it associates with poor clinical outcomes. However, molecular features associated with this sole monosomy subtype (-7 AML) which may give insights into the basis for its poor prognosis have not been characterized. In this study, we analyzed 36 cases of -7 AML for mutations in 81 leukemia/cancer-associated genes using a customized targeted next-generation sequencing panel (Miseq). Global gene and microRNA expression profiles were also determined using paired RNA and small RNA sequencing data...
October 26, 2016: Cancer Research
https://www.readbyqxmd.com/read/27765915/variable-but-consistent-pattern-of-meningioma-1-gene-mn1-expression-in-different-genetic-subsets-of-acute-myelogenous-leukaemia-and-its-potential-use-as-a-marker-for-minimal-residual-disease-detection
#8
Sonia Carturan, Jessica Petiti, Valentina Rosso, Chiara Calabrese, Elisabetta Signorino, Giada Bot-Sartor, Paolo Nicoli, Daniela Gallo, Enrico Bracco, Alessandro Morotti, Cristina Panuzzo, Enrico Gottardi, Francesco Frassoni, Giuseppe Saglio, Daniela Cilloni
Meningioma 1 (MN1) gene overexpression has been reported in acute myeloid leukaemia (AML) patients and identified as a negative prognostic factor. In order to characterize patients presenting gene overexpression and to verify if MN1 transcript could be a useful marker for minimal residual disease detection, MN1 was quantified in 136 AML patients with different cytogenetic risk and in 50 normal controls. In 20 patients bearing a fusion gene transcript suitable for minimal residual disease quantitative assessment and in 8 patients with NPM1 mutation, we performed a simultaneous analysis of MN1 and the fusion-gene transcript or NPM1 mutation during follow-up...
September 27, 2016: Oncotarget
https://www.readbyqxmd.com/read/27752371/myeloproliferative-neoplasm-or-reactive-process-a-rare-case-of-acute-myeloid-leukemia-and-transient-posttreatment-megakaryocytic-hyperplasia-with-jak-2-mutation
#9
Steven Wang, Jie Yan, Guangde Zhou, Rebecca Heintzelman, J Steve Hou
Myeloproliferative neoplasms (MPNs) are hematopoietic malignancies characterized by unchecked proliferation of differentiated myeloid cells. The most common BCR-ABL1-negative MPNs are polycythemia vera, essential thrombocythemia, and primary myelofibrosis. The discovery of JAK2 V617F mutation has improved our understanding of the molecular basis of MPN. The high frequency of JAK2 mutation in MPN makes JAK2 mutation testing an essential diagnostic tool and potential therapeutic target for MPN. Here, we present a rare case of a 34-year-old patient who was initially diagnosed with acute myeloid leukemia (AML) with mutated NPM1...
2016: Case Reports in Hematology
https://www.readbyqxmd.com/read/27748301/nucleophosmin-mutation-analysis-in-acute-myeloid-leukaemia-immunohistochemistry-as-a-surrogate-for-molecular-techniques
#10
Anita Chopra, Sushant Soni, Haraprasad Pati, Dev Kumar, Rahul Diwedi, Deepak Verma, Garima Vishwakama, Sameer Bakhshi, Suman Kumar, Ajay Gogia, Rajive Kumar
BACKGROUND & OBJECTIVES: Mutation of nucleophosmin (NPM1) gene in the absence of FLT3-ITD (FMS related tyrosine kinase 3 - internal tandem duplications) mutation carries a good prognosis in cytogenetically normal acute myeloid leukaemia (AML). NPM1, a multifunctional nucleolar phosphoprotein that shuttles between nucleus and cytoplasm, gets trapped in the cytoplasm when mutated. Immunohistochemical (IHC) demonstration of its aberrant cytoplasmic location (NPMc+) has been suggested as a simple substitute for the standard screening molecular method...
June 2016: Indian Journal of Medical Research
https://www.readbyqxmd.com/read/27736291/clinical-significance-of-galectin-3-in-patients-with-adult-acute-myeloid-leukemia-a-retrospective-cohort-study-with-long-term-follow-up-and-formulation-of-risk-scoring-system
#11
Na Gao, Wen-Zheng Yu, Nong-Jian Guo, Xue-Xia Wang, Jian-Rong Sun
Galectin-3 plays an increasingly important role in development and progression of tumor. However, little is known about the clinical impact of galectin-3 in non-acute promyelocytic leukemia (non-M3 AML). Peripheral blood of 298 patients with primary non-M3 AML and 30 normal donors was collected for measurement of galectin-3. Galectin-3 levels were significantly higher compared with the control group (p < .001). Patients with higher galectin-3 levels had lower CR rates (p = .001) and 1-year overall survival (OS) rates (p = ...
October 13, 2016: Leukemia & Lymphoma
https://www.readbyqxmd.com/read/27698101/accurate-medicine-indirect-targeting-of-npm1-mutated-aml
#12
Christopher S Hourigan, Peter D Aplan
Acute myeloid leukemia (AML) is now recognized to be an imprecise term that refers to a range of myeloid malignancies that have different genetical etiologies, clinical characteristics, and therapeutic sensitivities. Targeting the MLL1 and DOT1L histone modification complexes, both alone and in combination, showed activity against AML driven by a mutant NPM1 protein in several preclinical models and may represent a new treatment direction for this devastating disease. Cancer Discov; 6(10); 1087-9 ©2016 AACR...
October 2016: Cancer Discovery
https://www.readbyqxmd.com/read/27696203/all-trans-retinoic-acid-as-adjunct-to-intensive-treatment-in-younger-adult-patients-with-acute-myeloid-leukemia-results-of-the-randomized-amlsg-07-04-study
#13
Richard F Schlenk, Michael Lübbert, Axel Benner, Alexander Lamparter, Jürgen Krauter, Wolfgang Herr, Hans Martin, Helmut R Salih, Andrea Kündgen, Heinz-A Horst, Peter Brossart, Katharina Götze, David Nachbaur, Mohammed Wattad, Claus-Henning Köhne, Walter Fiedler, Martin Bentz, Gerald Wulf, Gerhard Held, Bernd Hertenstein, Hans Salwender, Verena I Gaidzik, Brigitte Schlegelberger, Daniela Weber, Konstanze Döhner, Arnold Ganser, Hartmut Döhner
The aim of this clinical trial was to evaluate the impact of all-trans retinoic acid (ATRA) in combination with chemotherapy and to assess the NPM1 status as biomarker for ATRA therapy in younger adult patients (18-60 years) with acute myeloid leukemia (AML). Patients were randomized for intensive chemotherapy with or without open-label ATRA (45 mg/m(2), days 6-8; 15 mg/m(2), days 9-21). Two cycles of induction therapy were followed by risk-adapted consolidation with high-dose cytarabine or allogeneic hematopoietic cell transplantation...
December 2016: Annals of Hematology
https://www.readbyqxmd.com/read/27689396/prognostic-nomogram-for-previously-untreated-adult-patients-with-acute-myeloid-leukemia
#14
Zhuojun Zheng, Xiaodong Li, Yuandong Zhu, Weiying Gu, Xiaobao Xie, Jingting Jiang
This study was designed to perform an acceptable prognostic nomogram for acute myeloid leukemia. The clinical data from 311 patients from our institution and 165 patients generated with Cancer Genome Atlas Research Network were reviewed. A prognostic nomogram was designed according to the Cox's proportional hazard model to predict overall survival (OS). To compare the capacity of the nomogram with that of the current prognostic system, the concordance index (C-index) was used to validate the accuracy as well as the calibration curve...
September 26, 2016: Oncotarget
https://www.readbyqxmd.com/read/27669739/the-human-nucleophosmin-1-mutation-a-inhibits-myeloid-differentiation-of-leukemia-cells-by-modulating-mir-10b
#15
Qin Zou, Shi Tan, Zailin Yang, Juan Wang, Jingrong Xian, Shuaishuai Zhang, Hongjun Jin, Liyuan Yang, Lu Wang, Ling Zhang
Mutations in the nucleophosmin 1 (NPM1) gene are the most frequent genetic alteration in acute myeloid leukemia (AML). Here, we showed that enforced expression of NPM1 mutation type A (NPM1-mA) inhibits myeloid differentiation of leukemia cells, whereas knockdown of NPM1-mA has the opposite effect. Our analyses of normal karyotype AML samples from The Cancer Genome Atlas (TCGA) dataset revealed that miR-10b is commonly overexpressed in NPM1-mutated AMLs. We also found high expression of miR-10b in primary NPM1-mutated AML blasts and NPM1-mA positive OCI-AML3 cells...
September 23, 2016: Oncotarget
https://www.readbyqxmd.com/read/27646892/-characterization-of-mutational-pattern-in-patients-with-ph-negative-myeloproliferative-neoplasms
#16
F Xing, Y N Lin, Q Sun, L Qin, Y J Jia, D L Zhang, K Ru
Objective: To characterize the molecular profile in patients with Ph negative myeloproliferative neoplasms (MPN) by exploring 49 gene mutations. Methods: Targeted gene sequencing were performed to analyze 49 MPN-associated genes in 51 patients with Ph negative MPN, of which CARL (exon 9), NPM1 (exon 12) and CEBPA (TAD, BZIP domains) were investigated by using Sanger sequencing simultaneously, while FLT3-ITD was assessed by PCR method. Results: Mutations were detected in 73.5% (36/49) of genes, and the mutational rates of JAK2-V617F, CALR (exon 9) and MPL were 60...
September 8, 2016: Zhonghua Bing Li Xue za Zhi Chinese Journal of Pathology
https://www.readbyqxmd.com/read/27643573/karyotype-plus-npm1-mutation-status-defines-a-group-of-elderly-patients-with-aml-%C3%A2-60-years-who-benefit-from-intensive-post-induction-consolidation-therapy
#17
Wolfgang R Sperr, Otto Zach, Iris Pöll, Susanne Herndlhofer, Paul Knoebl, Ansgar Weltermann, Berthold Streubel, Ulrich Jaeger, Michael Kundi, Peter Valent
Although it is generally appreciated that a subset of elderly patients with acute myeloid leukemia (AML) may benefit from intensive consolidation, little is known about variables predicting such benefit. We analyzed 192 consecutive patients with de novo AML aged ≥60 years who were treated with intensive chemotherapy. About 115 patients (60%) achieved complete hematologic remission (CR). Among several parameters, the karyotype was the only independent variable predicting CR (P < 0.05). About 92% (105/115) of the CR-patients received up to four consolidation cycles of intermediate dose ARA-C...
December 2016: American Journal of Hematology
https://www.readbyqxmd.com/read/27636548/acute-myeloid-leukemia-with-del-9q-is-characterized-by-frequent-mutations-of-npm1-dnmt3a-wt1-and-low-expression-of-tle4
#18
Tobias Herold, Klaus H Metzeler, Sebastian Vosberg, Luise Hartmann, Vindi Jurinovic, Sabrina Opatz, Nikola P Konstandin, Stephanie Schneider, Evelyn Zellmeier, Bianka Ksienzyk, Alexander Graf, Stefan Krebs, Helmut Blum, Maria Cristina Sauerland, Thomas Büchner, Wolfgang E Berdel, Bernhard J Wörmann, Ulrich Mansmann, Wolfgang Hiddemann, Stefan K Bohlander, Karsten Spiekermann, Philipp A Greif
Deletions of the long arm of chromosome 9 [del(9q)] are a rare but recurring aberration in acute myeloid leukemia (AML). Del(9q) can be found as the sole abnormality or in combination with other cytogenetic aberrations such as t(8;21) and t(15;17). TLE1 and TLE4 were identified to be critical genes contained in the 9q region. We performed whole exome sequencing of 5 patients with del(9q) as the sole abnormality followed by targeted amplicon sequencing of 137 genes of 26 patients with del(9q) as sole or combined with other aberrations...
January 2017: Genes, Chromosomes & Cancer
https://www.readbyqxmd.com/read/27626217/persistent-dnmt3a-mutation-burden-in-dnmt3a-mutated-adult-cytogenetically-normal-acute-myeloid-leukemia-patients-in-long-term-remission
#19
Yanjun Sun, Hongjie Shen, Ting Xu, Zhen Yang, Huiying Qiu, Aining Sun, Suning Chen, Depei Wu, Yang Xu
DNMT3A mutations are frequent in cytogenetically normal acute myeloid leukemia (CN-AML) patients and can be present many years before the disease develops. However, the clinical significance of DNMT3A mutation burden in CN-AML remains unclear. In this study, 81 DNMT3A mutated adult CN-AML patients in their first complete remission (CR) were enrolled at our center from March 2005 to May 2015. All patients were identified as having DNMT3A exon 23 mutations, and R882H was the most frequent variant (n=49, 60.49%)...
October 2016: Leukemia Research
https://www.readbyqxmd.com/read/27581357/inv-16-and-npm1mut-amls-engraft-human-cytokine-knock-in-mice
#20
Jana M Ellegast, Philipp J Rauch, Larisa V Kovtonyuk, Rouven Müller, Ulrich Wagner, Yasuyuki Saito, Nicole Wildner-Verhey van Wijk, Christine Fritz, Anahita Rafiei, Veronika Lysenko, Ewa Dudkiewicz, Alexandre P Theocharides, Davide Soldini, Jeroen S Goede, Richard A Flavell, Markus G Manz
Favorable-risk human acute myeloid leukemia (AML) engrafts poorly in currently used immunodeficient mice, possibly because of insufficient environmental support of these leukemic entities. To address this limitation, we here transplanted primary human AML with isolated nucleophosmin (NPM1) mutation and AML with inv(16) in mice in which human versions of genes encoding cytokines important for myelopoiesis (macrophage colony-stimulating factor [M-CSF], interleukin-3, granulocyte-macrophage colony-stimulating factor, and thrombopoietin) were knocked into their respective mouse loci...
October 27, 2016: Blood
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