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NPM1 mutation

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
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
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
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
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
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...
October 3, 2016: Annals of Hematology
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
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
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
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 analysed 192 consecutive patients with de novo AML aged ≥60 years who were treated with intensive chemotherapy. One-hundred-fifteen patients (60%) achieved complete hematologic remission (CR). Among several parameters, the karyotype was the only independent variable predicting CR (p<0.05). Ninety-two percent (105/115) of the CR-patients received up to 4 consolidation cycles of intermediate dose ARA-C...
September 19, 2016: American Journal of Hematology
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...
September 16, 2016: Genes, Chromosomes & Cancer
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
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 mostly used immuno-deficient mice, possibly due to insufficient environmental support of these leukemic entities. To address this limitation, we here transplanted primary human AML with isolated NPM1 mutation and AML with inv(16) in mice in which human versions of genes encoding cytokines important for myelopoiesis (M-CSF, IL-3, GM-CSF, Thrombopoietin) were knocked into their respective mouse loci. NPM1(mut) AML engrafted with higher efficacy in cytokine knock-in mice and showed a trend towards higher bone marrow engraftment levels in comparison to NSG mice...
August 31, 2016: Blood
Emna Abdelhamid, Sawsen Besbes, Aline Renneville, Olivier Nibourel, Nathalie Helevaut, Claude Preudhomme, Zohra Soua
BACKGROUND: With the growing importance of minimal residual disease (MRD) monitoring and the recent discover of IDH mutations in acute myeloid leukemia (AML), the quantification of this molecular marker provides the possibility to monitor the disease progression and the therapy efficacy. OBJECTIVE: The aim of this study is to assess the MRD in AML for the first time with IDH1 and IDH2 gene mutations in 15 AML patients. METHODS: We have screened R132 IDH1, R140 IDH2 and R172 IDH2 mutations by PCR amplification and direct sequencing and we have quantified them for the first time by RQ-PCR using reverse primers modified by an LNA...
March 2016: La Tunisie Médicale
Thomas Boyer, Soizic Guihard, Christophe Roumier, Pauline Peyrouze, Fanny Gonzales, Céline Berthon, Bruno Quesnel, Claude Preudhomme, Hélène Behal, Alain Duhamel, Catherine Roche-Lestienne, Meyling Cheok
CD81 is a cell surface protein which belongs to the tetraspanin family. While in multiple myeloma its expression on plasma cells is associated with worse prognosis, this has not yet been explored in acute myeloid leukemia (AML). We measured membrane expression of CD81 on AML cells at diagnosis, evaluated its association with AML characteristics and its influence on patient outcome after intensive chemotherapy in a cohort of 134 patients. CD81 was detected in 92/134 (69%) patients. Patients with AML expressing CD81 had elevated leukocyte count (P=0...
August 22, 2016: Oncotarget
Joseph K Box, Nicolas Paquet, Mark N Adams, Didier Boucher, Emma Bolderson, Kenneth J O'Byrne, Derek J Richard
Nucleophosmin (NPM1) is a critical cellular protein that has been implicated in a number of pathways including mRNA transport, chromatin remodeling, apoptosis and genome stability. NPM1 function is a critical requirement for normal cellular biology as is underlined in cancer where NPM1 is commonly overexpressed, mutated, rearranged and sporadically deleted. Consistent with a multifunctional role within the cell, NPM1 can function not only as a proto-oncogene but also as a tumor suppressor. The aim of this review is to look at the less well-described role of NPM1 in the DNA repair pathways as well as the role of NPM1 in the regulation of apoptosis and its mutation in cancers...
2016: BMC Molecular Biology
Michael W M Kühn, Evelyn Song, Zhaohui Feng, Amit Sinha, Chun-Wei Chen, Aniruddha J Deshpande, Monica Cusan, Noushin Farnoud, Annalisa Mupo, Carolyn Grove, Richard Koche, James E Bradner, Elisa de Stanchina, George S Vassiliou, Takayuki Hoshii, Scott A Armstrong
: Homeobox (HOX) proteins and the receptor tyrosine kinase FLT3 are frequently highly expressed and mutated in acute myeloid leukemia (AML). Aberrant HOX expression is found in nearly all AMLs that harbor a mutation in the Nucleophosmin (NPM1) gene, and FLT3 is concomitantly mutated in approximately 60% of these cases. Little is known about how mutant NPM1 (NPM1(mut)) cells maintain aberrant gene expression. Here, we demonstrate that the histone modifiers MLL1 and DOT1L control HOX and FLT3 expression and differentiation in NPM1(mut) AML...
October 2016: Cancer Discovery
Pasqualina Liana Scognamiglio, Concetta Di Natale, Marilisa Leone, Roberta Cascella, Cristina Cecchi, Lisa Lirussi, Giulia Antoniali, Domenico Riccardi, Giancarlo Morelli, Gianluca Tell, Fabrizio Chiti, Daniela Marasco
Nucleophosmin (NPM1) is a multifunctional protein that is implicated in the pathogenesis of several human malignancies. To gain insight into the role of isolated fragments of NPM1 in its biological activities, we dissected the C-terminal domain (CTD) into its helical fragments. Here we focus the attention on the third helix of the NPM1-CTD in its wild-type (H3 wt) and AML-mutated (H3 mutA and H3 mutE) sequences. Conformational studies, by means of CD and NMR spectroscopies, showed that the H3 wt peptide was partially endowed with an α-helical structure, but the AML-sequences exhibited a lower content of this conformation, particularly the H3 mutA peptide...
August 1, 2016: Oncotarget
Nasrin Alizad Ghandforoush, Bahram Chahardouli, Shahrbano Rostami, Habibeh Ghadimi, Ali Ghasemi, Kamran Alimoghaddam, Ardeshir Ghavamzadeh, Fatemeh Nadali
BACKGROUND: Minimal residual disease (MRD) tests provide early identification of hematologic relapse and timely management of acute myeloid leukemia (AML) patients. Approximately, 50% of AML patients do not have clonal chromosomal aberrations and categorize as a cytogenetically normal acute myeloid leukemia (CN-AML). About 60% of adult CN-AML has a mutation in exon 12 of NPM1 gene. This mutation is specific for malignant clone and potentially is a good marker of MRD. In this retrospective study, we set up a quantitative test for quantifying NPM1 type A mutation and AML patients carrying this mutation at the time of diagnosis, were followed-up...
July 1, 2016: International Journal of Hematology-oncology and Stem Cell Research
Elisa Barbieri, Gianluca Deflorian, Federica Pezzimenti, Debora Valli, Marco Saia, Natalia Meani, Alicja M Gruszka, Myriam Alcalay
Nucleophosmin (NPM1) is a ubiquitous multifunctional phosphoprotein with both oncogenic and tumor suppressor functions. Mutations of the NPM1 gene are the most frequent genetic alterations in acute myeloid leukemia (AML) and result in the expression of a mutant protein with aberrant cytoplasmic localization, NPMc+. Although NPMc+ causes myeloproliferation and AML in animal models, its mechanism of action remains largely unknown. Here we report that NPMc+ activates canonical Wnt signaling during the early phases of zebrafish development and determines a Wnt-dependent increase in the number of progenitor cells during primitive hematopoiesis...
July 28, 2016: Oncotarget
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