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NPM1 mutation

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https://www.readbyqxmd.com/read/28618016/abcg2-and-cd200-define-patients-at-high-risk-of-relapse-in-enl-favorable-subgroup-of-aml
#1
Mario Tiribelli, Antonella Geromin, Margherita Cavallin, Sara Di Giusto, Erica Simeone, Renato Fanin, Daniela Damiani
OBJECTIVE: overexpression of ABCG2 and CD200 have been independently associated with poor outcome in acute myeloid leukemia (AML). However, no data are available on the role of these two factors in patients with core binding factor (CBF) positive or FLT3-negative / NPM1-mutated cytogenetically normal (CN) AML. METHODS: we analyzed 65 adult AML patients with CBF+ (n=16) or FLT3-/NPM1+ CN (n=49), evaluating clinical and biological factors associated with complete remission attainment, leukemia-free survival (LFS) and overall survival (OS)...
June 15, 2017: European Journal of Haematology
https://www.readbyqxmd.com/read/28581462/dynamics-of-molecular-response-in-aml-patients-with-npm1-and-flt3-mutations-undergoing-allogeneic-stem-cell-transplant
#2
R Salem, R Massoud, B Haffar, R Mahfouz, A Bazarbachi, J El-Cheikh
No abstract text is available yet for this article.
June 5, 2017: Bone Marrow Transplantation
https://www.readbyqxmd.com/read/28574487/cd123-target-validation-and-preclinical-evaluation-of-adcc-activity-of-anti-cd123-antibody-csl362-in-combination-with-nks-from-aml-patients-in-remission
#3
L H Xie, M Biondo, S J Busfield, A Arruda, X Yang, G Vairo, M D Minden
Despite the heterogeneity of acute myeloid leukemia (AML), overexpression of the interleukin-3 receptor-α (CD123) on both the more differentiated leukemic blast and leukemic stem cells (LSCs) provides a therapeutic target for antibody treatment. Here we present data on the potential clinical activity of the monoclonal antibody CSL362, which binds to CD123 with high affinity. We first validated the expression of CD123 by 100% (52/52) of patient samples and the correlation of NPM1 and FLT3-ITD mutations with the high frequency of CD123 in AML...
June 2, 2017: Blood Cancer Journal
https://www.readbyqxmd.com/read/28569789/knockdown-of-mir-128a-induces-lin28a-expression-and-reverts-myeloid-differentiation-blockage-in-acute-myeloid-leukemia
#4
Luciana De Luca, Stefania Trino, Ilaria Laurenzana, Daniela Tagliaferri, Geppino Falco, Vitina Grieco, Gabriella Bianchino, Filomena Nozza, Valentina Campia, Francesca D'Alessio, Francesco La Rocca, Antonella Caivano, Oreste Villani, Daniela Cilloni, Pellegrino Musto, Luigi Del Vecchio
Lin28A is a highly conserved RNA-binding protein that concurs to control the balance between stemness and differentiation in several tissue lineages. Here, we report the role of miR-128a/Lin28A axis in blocking cell differentiation in acute myeloid leukemia (AML), a genetically heterogeneous disease characterized by abnormally controlled proliferation of myeloid progenitor cells accompanied by partial or total inability to undergo terminal differentiation. First, we found Lin28A underexpressed in blast cells from AML patients and AML cell lines as compared with CD34+ normal precursors...
June 1, 2017: Cell Death & Disease
https://www.readbyqxmd.com/read/28557599/validation-of-oncopanel-a-targeted-next-generation-sequencing-assay-for-the-detection-of-somatic-variants-in-cancer
#5
Elizabeth P Garcia, Alissa Minkovsky, Yonghui Jia, Matthew D Ducar, Priyanka Shivdasani, Xin Gong, Azra H Ligon, Lynette M Sholl, Frank C Kuo, Laura E MacConaill, Neal I Lindeman, Fei Dong
CONTEXT: - The analysis of somatic mutations across multiple genes in cancer specimens may be used to aid clinical decision making. The analytical validation of targeted next-generation sequencing panels is important to assess accuracy and limitations. OBJECTIVE: - To report the development and validation of OncoPanel, a custom targeted next-generation sequencing assay for cancer. DESIGN: - OncoPanel was designed for the detection of single-nucleotide variants, insertions and deletions, copy number alterations, and structural variants across 282 genes with evidence as drivers of cancer biology...
June 2017: Archives of Pathology & Laboratory Medicine
https://www.readbyqxmd.com/read/28536276/persistent-immune-stimulation-exacerbates-genetically-driven-myeloproliferative-disorders-via-stromal-remodeling
#6
Claudio Tripodo, Alessia Burocchi, Pier Paolo Piccaluga, Claudia Chiodoni, Paola Portararo, Barbara Cappetti, Laura Botti, Alessandro Gulino, Alessandro Isidori, Arcangelo Liso, Giuseppe Visani, Maria Paola Martelli, Brunangelo Falini, Pier Paolo Pandolfi, Mario P Colombo, Sabina Sangaletti
Systemic immune stimulation has been associated with increased risk of myeloid malignancies, but the pathogenic link is unknown. We demonstrate in animal models that experimental systemic immune activation alters the bone marrow stromal microenvironment, disarranging extracellular matrix (ECM) microarchitecture, with down-regulation of SPARC and collagen-I and induction of complement activation. These changes were accompanied by a decrease in Treg frequency and by an increase in activated effector T cells. Under these conditions, hematopoietic precursors harboring nucleophosmin-1 (NPM1) mutation generated myeloid cells unfit for normal hematopoiesis but prone to immunogenic death, leading to neutrophil extracellular trap (NET) formation...
May 23, 2017: Cancer Research
https://www.readbyqxmd.com/read/28525762/minimal-residual-disease-monitoring-of-acute-myeloid-leukemia-by-massively-multiplex-digital-pcr-in-patients-with-npm1-mutations
#7
Nuria Mencia-Trinchant, Yang Hu, Maria Antonina Alas, Fatima Ali, Bas J Wouters, Sangmin Lee, Ellen K Ritchie, Pinkal Desai, Monica L Guzman, Gail J Roboz, Duane C Hassane
The presence of minimal residual disease (MRD) is widely recognized as a powerful predictor of therapeutic outcome in acute myeloid leukemia (AML), but methods of measurement and quantification of MRD in AML are not yet standardized in clinical practice. There is an urgent, unmet need for robust and sensitive assays that can be readily adopted as real-time tools for disease monitoring. NPM1 frameshift mutations are an established MRD marker present in half of patients with cytogenetically normal AML. However, detection is complicated by the existence of hundreds of potential frameshift insertions, clonal heterogeneity, and absence of sequence information when the NPM1 mutation is identified using capillary electrophoresis...
May 16, 2017: Journal of Molecular Diagnostics: JMD
https://www.readbyqxmd.com/read/28481984/the-dna-damage-response-ddr-is-induced-by-the-c9orf72-repeat-expansion-in-amyotrophic-lateral-sclerosis
#8
Manal A Farg, Anna Konopka, Kai Ying Soo, Daisuke Ito, Julie D Atkin
Amyotrophic lateral sclerosis (ALS) is a rapidly progressing neurodegenerative disease affecting motor neurons. Hexanucleotide (GGGGCC) repeat expansions in a non-coding region of C9orf72 are the major cause of familial ALS and frontotemporal dementia (FTD) worldwide. The C9orf72 repeat expansion undergoes repeat-associated non-ATG (RAN) translation to produce five dipeptide repeat proteins (DRPs), including poly(GR) and poly(PR). Whilst it remains unclear how mutations in C9orf72 lead to neurodegeneration in ALS/FTD, dysfunction to the nucleolus and R loop formation are implicated as pathogenic mechanisms...
May 8, 2017: Human Molecular Genetics
https://www.readbyqxmd.com/read/28475434/enhancing-acute-myeloid-leukemia-therapy-monitoring-response-using-residual-disease-testing-as-a-guide-to-therapeutic-decision-making
#9
REVIEW
Benjamin Tomlinson, Hillard M Lazarus
Current standards for monitoring the response of acute myeloid leukemia (AML) are based on morphologic assessments of the bone marrow and recovery of peripheral blood counts. A growing experience is being developed to enhance the detection of small amounts of AML, or minimal residual disease (MRD). Areas covered: Available techniques include multi-color flow cytometry (MFC) of leukemia associated immunophenotypes (LAIP), quantitative reverse transcriptase polymerase chain reaction (QRT-PCR) for detecting fusion and mutated genes (RUNX1-RUNX1T1, CBFB-MYH11, and NPM1), overexpression of genes such as WT1, and next generation sequencing (NGS) for MRD...
June 2017: Expert Review of Hematology
https://www.readbyqxmd.com/read/28473620/prognostic-and-biologic-significance-of-long-non-coding-rna-profiling-in-younger-adults-with-cytogenetically-normal-acute-myeloid-leukemia
#10
Dimitrios Papaioannou, Deedra Nicolet, Stefano Volinia, Krzysztof Mrózek, Pearlly Yan, Ralf Bundschuh, Andrew J Carroll, Jessica Kohlschmidt, William Blum, Bayard L Powell, Geoffrey L Uy, Jonathan E Kolitz, Eunice S Wang, Ann-Kathrin Eisfeld, Shelley J Orwick, David M Lucas, Michael A Caligiuri, Richard M Stone, John C Byrd, Ramiro Garzon, Clara D Bloomfield
Long non-coding RNAs are a novel class of RNA molecules, which are increasingly recognized as important molecular players in solid and hematologic malignancies. Herein we investigated whether long non-coding RNA expression is associated with clinical and molecular features, as well as outcome of younger adults (aged <60 years) with de novo cytogenetically normal acute myeloid leukemia. Whole transcriptome profiling (RNA-seq) was performed in a training (n=263) and a validation set (n=114). Using the training set, we identified 24 long non-coding RNAs associated with event-free survival...
May 4, 2017: Haematologica
https://www.readbyqxmd.com/read/28471807/deguelin-induced-differentiation-of-mutated-npm1-acute-myeloid-leukemia-in-vivo-and-in-vitro
#11
Xia Zhang, Zichu Zhao, Sha Yi, Lu Wen, Jing He, Jingyu Hu, Jun Ruan, Jun Fang, Yan Chen
Nucleophosmin (NPM1), a restricted nucleolar localization protein, shuttles between the nucleus and the cytoplasm. Mutated (Mt)-NPM1 protein, which has aberrant cytoplasmic dislocation of nucleophosmin, occurs in approximately one-third of acute myeloid leukemia cases. Deguelin, a rotenoid isolated from several plant species, is a strong antitumor agent. NOD/SCID mice xenografted with human Mt-NPM1 OCI/AML3 cell lines served as in-vivo models. Wright-Giemsa staining and flow cytometry analysis were used for differentiation assays...
May 3, 2017: Anti-cancer Drugs
https://www.readbyqxmd.com/read/28456748/reprogramming-acute-myeloid-leukemia-into-sensitivity-for-retinoic-acid-driven-differentiation
#12
REVIEW
Noortje van Gils, Han J M P Verhagen, Linda Smit
The success of all-trans retinoic acid (ATRA) therapy for acute promyelocytic leukemia (APL) provides a rationale for using retinoic acid (RA)-based therapy for other subtypes of acute myeloid leukemia (AML). Recently, several studies showed that ATRA may drive leukemic cells efficiently into differentiation and/or apoptosis in a subset of AML patients with an NPM1 mutation, an FLT3-ITD, an IDH1 mutation, and an overexpression of EVI-1. Because not all patients within these molecular subgroups respond to ATRA and clinical trials that tested ATRA response in non-APL AML patients have had disappointing results, the identification of additional biomarkers may help to identify patients who strongly respond to ATRA-based therapy...
April 27, 2017: Experimental Hematology
https://www.readbyqxmd.com/read/28452374/prognostic-significance-of-huntingtin-interacting-protein-1-expression-on-patients-with-acute-myeloid-leukemia
#13
Jinghan Wang, Mengxia Yu, Qi Guo, Qiuling Ma, Chao Hu, Zhixin Ma, Xiufeng Yin, Xia Li, Yungui Wang, Hanzhang Pan, Dongmei Wang, Jiansong Huang, Haitao Meng, Hongyan Tong, Wenbin Qian, Jie Jin
Huntingtin interacting protein 1 (HIP1) is an endocytic protein which is overexpressed in a variety of human cancers and involved in cancer-causing translocation in leukemia. However, the prognostic impact of HIP1 expression on AML remains unclear. In this study, quantification of HIP1 transcript by real-time quantitative PCR in bone marrow blasts was performed in 270 AML patients. As a result, high HIP1 expression was seen more frequently in older patients, M4/M5 morphology and genes of NPM1 and DNMT3A mutations, and underrepresented in favorable karyotype subgroups and CEBPA double allele mutations in our AML patients...
April 28, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28447422/minimal-residual-disease-in-acute-myelogenous-leukemia
#14
REVIEW
N M Cruz, N Mencia-Trinchant, D C Hassane, M L Guzman
Treatment of acute myelogenous leukemia (AML) over the past four decades remains mostly unchanged and the prognosis for the majority of patients remains poor. Most of the significant advances that have been observed are in defining cytogenetic abnormalities, as well as the genetic and epigenetic profiles of AML patients. While new cytogenetic and genetic aberrations such as the FLT3-ITD and NPM1 mutations are able to guide prognosis for the majority of patients with AML, outcomes are still dismal and relapse rates remain high...
May 2017: International Journal of Laboratory Hematology
https://www.readbyqxmd.com/read/28435324/symptomatic-central-nervous-system-involvement-in-adult-patients-with-acute-myeloid-leukemia
#15
Nael Alakel, Friedrich Stölzel, Brigitte Mohr, Michael Kramer, Uta Oelschlägel, Christoph Röllig, Martin Bornhäuser, Gerhard Ehninger, Markus Schaich
INTRODUCTION: Acute myeloid leukemia (AML) rarely involves the central nervous system (CNS). Little is known about the clinical course in adult AML patients since most studies examined pediatric patients. Therefore, this study analyzed the data of patients treated in three prospective trials of the "Study Alliance Leukemia" (SAL) study group for CNS involvement. METHODS: In all, 3,261 AML patients included in the prospective AML96, AML2003, and AML60+ trials of the SAL study group were analyzed...
2017: Cancer Management and Research
https://www.readbyqxmd.com/read/28424161/response-and-progression-on-midostaurin-in-advanced-systemic-mastocytosis-kit-d816v-and-other-molecular-markers
#16
Mohamad Jawhar, Juliana Schwaab, Nicole Naumann, Hans-Peter Horny, Karl Sotlar, Torsten Haferlach, Georgia Metzgeroth, Alice Fabarius, Peter Valent, Wolf-Karsten Hofmann, Nicholas C P Cross, Manja Meggendorfer, Andreas Reiter
In advanced systemic mastocytosis (advSM), disease evolution is often triggered by activating KIT mutations (D816V in >80% of cases) and by additional mutations, e.g. in SRSF2, ASXL1 and/or RUNX1 (S/A/R(pos), >60% of cases). In a recently reported phase-II-study, midostaurin, a multikinase/KIT inhibitor, demonstrated an overall response rate (ORR) of 60% in advSM but biomarkers predictive of response are lacking. We evaluated the impact of molecular markers (KIT D816V, S/A/R(pos)) at baseline and during follow-up in 38 midostaurin-treated advSM patients...
April 19, 2017: Blood
https://www.readbyqxmd.com/read/28407515/high-cd200-expression-is-associated-with-poor-prognosis-in-cytogenetically-normal-acute-myeloid-leukemia-even-in-flt3-itd-npm1-patients
#17
Mario Tiribelli, Donatella Raspadori, Antonella Geromin, Margherita Cavallin, Santina Sirianni, Erica Simeone, Monica Bocchia, Renato Fanin, Daniela Damiani
Overexpression of CD200, a trans-membrane protein belonging to the immunoglobulin superfamily, has been associated with poor prognosis in patients with acute myeloid leukemia (AML). As few data are available in the subset of cytogenetically-normal (CN) AML, we retrospectively evaluated the correlations between CD200 expression and response to therapy in a series of 139 adults with CN-AML. CD200 was expressed in 67/139 (48%) cases; 18 of them (28%) expressed CD200 at high intensity. No differences in CD200 expression rate were observed according to age, WBC count, type of leukemia, FLT3 or NMP1 mutation, and CD56 expression...
July 2017: Leukemia Research
https://www.readbyqxmd.com/read/28384310/localization-of-aml-related-nucleophosmin-mutant-depends-on-its-subtype-and-is-highly-affected-by-its-interaction-with-wild-type-npm
#18
Barbora Brodská, Markéta Kráčmarová, Aleš Holoubek, Kateřina Kuželová
Mutations of the gene for nucleophosmin (NPM1) are the most frequent genetic aberration in patients with acute myeloid leukemia (AML). The mechanism of leukemic transformation in this leukemia subtype is not fully understood, but aberrant cytoplasmic localization of mutated NPM (NPMmut) is widely considered as an important factor for leukemia manifestation. We analyzed the subcellular localization of three types of NPM with a C-terminal mutation (A, B and E). Genes for the individual NPM forms were fused with a gene for one of fluorescent protein variants in plasmids, which were transfected into three cell lines with different endogenous NPM expression...
2017: PloS One
https://www.readbyqxmd.com/read/28380436/classification-of-pediatric-acute-myeloid-leukemia-based-on-mirna-expression-profiles
#19
Askar Obulkasim, Jenny E Katsman-Kuipers, Lonneke Verboon, Mathijs Sanders, Ivo Touw, Mojca Jongen-Lavrencic, Rob Pieters, Jan-Henning Klusmann, C Michel Zwaan, Marry M van den Heuvel-Eibrink, Maarten Fornerod
Pediatric acute myeloid leukemia (AML) is a heterogeneous disease with respect to biology as well as outcome. In this study, we investigated whether known biological subgroups of pediatric AML are reflected by a common microRNA (miRNA) expression pattern. We assayed 665 miRNAs on 165 pediatric AML samples. First, unsupervised clustering was performed to identify patient clusters with common miRNA expression profiles. Our analysis unraveled 14 clusters, seven of which had a known (cyto-)genetic denominator. Finally, a robust classifier was constructed to discriminate six molecular aberration groups: 11q23-rearrangements, t(8;21)(q22;q22), inv(16)(p13q22), t(15;17) (q21;q22), NPM1 and CEBPA mutations...
May 16, 2017: Oncotarget
https://www.readbyqxmd.com/read/28370339/long-term-impact-of-hyperleukocytosis-in-newly-diagnosed-acute-myeloid-leukemia-patients-undergoing-allogeneic-stem-cell-transplantation-an-analysis-from-the-acute-leukemia-working-party-of-the-ebmt
#20
Jonathan Canaani, Myriam Labopin, Gerard Socié, Anne Nihtinen, Anne Huynh, Jan Cornelissen, Eric Deconinck, Tobias Gedde-Dahl, Edouard Forcade, Patrice Chevallier, Jean H Bourhis, Didier Blaise, Mohamad Mohty, Arnon Nagler
Up to 20% of acute myeloid leukemia (AML) patients present initially with hyperleukocytosis, placing them at increased risk for early mortality during induction. Yet, it is unknown whether hyperleukocytosis still retains prognostic value for AML patients undergoing hematopoietic stem cell transplantation (HSCT). Furthermore, it is unknown whether hyperleukocytosis holds prognostic significance when modern molecular markers such as FLT3-ITD and NPM1 are accounted for. To determine whether hyperleukocytosis is an independent prognostic factor influencing outcome in transplanted AML patients we performed a retrospective analysis using the registry of the acute leukemia working party of the European Society of Blood and Marrow Transplantation...
March 28, 2017: American Journal of Hematology
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