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https://www.readbyqxmd.com/read/29453396/bone-marrow-lympho-myeloid-malfunction-in-obesity-requires-precursor-cell-autonomous-tlr4
#1
Ailing Liu, Minhui Chen, Rashmi Kumar, Maja Stefanovic-Racic, Robert M O'Doherty, Ying Ding, Willi Jahnen-Dechent, Lisa Borghesi
Obesity, a prevalent condition in adults and children, impairs bone marrow (BM) function. However, the underlying mechanisms are unclear. Here, we show that obese mice exhibit poor emergency immune responses in a toll-like receptor 4 (TLR4)-dependent manner. Canonical myeloid genes (Csf1r, Spi1, Runx1) are enhanced, and lymphoid genes (Flt3, Tcf3, Ebf1) are reduced. Using adoptive transfer and mixed BM chimera approaches we demonstrate that myeloid>lymphoid bias arises after 6 weeks of high-fat diet and depends on precursor cell-autonomous TLR4...
February 16, 2018: Nature Communications
https://www.readbyqxmd.com/read/29438697/ezh2-and-runx1-mutations-collaborate-to-initiate-lympho-myeloid-leukemia-in-early-thymic-progenitors
#2
Christopher A G Booth, Nikolaos Barkas, Wen Hao Neo, Hanane Boukarabila, Elizabeth J Soilleux, George Giotopoulos, Noushin Farnoud, Alice Giustacchini, Neil Ashley, Joana Carrelha, Lauren Jamieson, Deborah Atkinson, Tiphaine Bouriez-Jones, Rab K Prinjha, Thomas A Milne, David T Teachey, Elli Papaemmanuil, Brian J P Huntly, Sten Eirik W Jacobsen, Adam J Mead
Lympho-myeloid restricted early thymic progenitors (ETPs) are postulated to be the cell of origin for ETP leukemias, a therapy-resistant leukemia associated with frequent co-occurrence of EZH2 and RUNX1 inactivating mutations, and constitutively activating signaling pathway mutations. In a mouse model, we demonstrate that Ezh2 and Runx1 inactivation targeted to early lymphoid progenitors causes a marked expansion of pre-leukemic ETPs, showing transcriptional signatures characteristic of ETP leukemia. Addition of a RAS-signaling pathway mutation (Flt3-ITD) results in an aggressive leukemia co-expressing myeloid and lymphoid genes, which can be established and propagated in vivo by the expanded ETPs...
February 12, 2018: Cancer Cell
https://www.readbyqxmd.com/read/29437468/dual-flt3-topk-inhibitor-with-activity-against-flt3-itd-secondary-mutations-potently-inhibits-acute-myeloid-leukemia-cell-lines
#3
Neetu Dayal, Clement Opoku-Temeng, Delmis E Hernandez, Moloud Aflaki Sooreshjani, Brandon A Carter-Cooper, Rena G Lapidus, Herman O Sintim
AIM: Approximately 30% of acute myeloid leukemia (AML) patients carry FLT3 tyrosine kinase domain (TKD) mutations or internal tandem duplication (FLT3-ITD). Currently there is a paucity of compounds that are active against drug-resistant FLT3-ITD, which contains secondary mutations in the TKD, mainly at residues D835/F691. RESULTS: HSD1169, a novel compound, is active against FLT3-ITD (D835 or F691). HSD1169 is also active against T-LAK cell-originated protein kinase (TOPK), a collaborating kinase that is highly expressed in AML cell lines...
February 13, 2018: Future Medicinal Chemistry
https://www.readbyqxmd.com/read/29433077/characterization-and-expression-of-dec205-in-the-cdc1-and-cdc2-subsets-of-porcine-dendritic-cells-from-spleen-tonsil-and-submaxillary-and-mesenteric-lymph-nodes
#4
Héctor Parra-Sánchez, Lucinda Puebla-Clark, Mónica Reséndiz, Olivia Valenzuela, Jesús Hernández
Conventional dendritic cells (cDCs) are divided into the following different subtypes: cDC1, which promotes a Th1 response, and cDC2, which stimulates a Th2 and Th17 response. These cells have not been characterized in porcine lymphoid tissues. DEC205 is a receptor that increases antigen presentation and allows DCs to cross-present antigens. The objectives of this work were to characterize cDCs subsets in the tonsil, submaxillary and mesenteric lymph nodes and spleen lymphoid tissues and to determine their expression of DEC205 by flow cytometry...
February 9, 2018: Molecular Immunology
https://www.readbyqxmd.com/read/29432313/cup-like-blasts-in-2-pediatric-patients-with-npm-1-positive-acute-myeloid-leukemia
#5
Özlem Tüfekçi, Melek Erdem, Hale Ören, Şebnem Yilmaz
Cup-like phenotype is defined in some subtypes of acute myeloid leukemia (AML) and have been associated with NPM-1 and/or FLT3-ITD positivity in the presence of normal karyotype in >60% of patients. Herein we present two pediatric AML-M1 patients with cuplike nuclear morphology and NPM-1 positivity. Both patients were negative for FLT3-ITD mutation. NPM-1 mutation and FLT3-ITD mutation should be kept in mind in AML patients with cup-like blast morphology as these two mutations are important molecular markers for prognosis, risk group classification and also for response to treatment...
February 9, 2018: Journal of Pediatric Hematology/oncology
https://www.readbyqxmd.com/read/29431743/sorafenib-promotes-graft-versus-leukemia-activity-in-mice-and-humans-through-il-15-production-in-flt3-itd-mutant-leukemia-cells
#6
Nimitha R Mathew, Francis Baumgartner, Lukas Braun, David O'Sullivan, Simone Thomas, Miguel Waterhouse, Tony A Müller, Kathrin Hanke, Sanaz Taromi, Petya Apostolova, Anna L Illert, Wolfgang Melchinger, Sandra Duquesne, Annette Schmitt-Graeff, Lena Osswald, Kai-Li Yan, Arnim Weber, Sonia Tugues, Sabine Spath, Dietmar Pfeifer, Marie Follo, Rainer Claus, Michael Lübbert, Christoph Rummelt, Hartmut Bertz, Ralph Wäsch, Johanna Haag, Andrea Schmidts, Michael Schultheiss, Dominik Bettinger, Robert Thimme, Evelyn Ullrich, Yakup Tanriver, Giang Lam Vuong, Renate Arnold, Philipp Hemmati, Dominik Wolf, Markus Ditschkowski, Cordula Jilg, Konrad Wilhelm, Christian Leiber, Sabine Gerull, Jörg Halter, Claudia Lengerke, Thomas Pabst, Thomas Schroeder, Guido Kobbe, Wolf Rösler, Soroush Doostkam, Stephan Meckel, Kathleen Stabla, Stephan K Metzelder, Sebastian Halbach, Tilman Brummer, Zehan Hu, Joern Dengjel, Björn Hackanson, Christoph Schmid, Udo Holtick, Christof Scheid, Alexandros Spyridonidis, Friedrich Stölzel, Rainer Ordemann, Lutz P Müller, Flore Sicre-de-Fontbrune, Gabriele Ihorst, Jürgen Kuball, Jan E Ehlert, Daniel Feger, Eva-Maria Wagner, Jean-Yves Cahn, Jacqueline Schnell, Florian Kuchenbauer, Donald Bunjes, Ronjon Chakraverty, Simon Richardson, Saar Gill, Nicolaus Kröger, Francis Ayuk, Luca Vago, Fabio Ciceri, Antonia M Müller, Takeshi Kondo, Takanori Teshima, Susan Klaeger, Bernhard Kuster, Dennis Dong Hwan Kim, Daniel Weisdorf, Walter van der Velden, Daniela Dörfel, Wolfgang Bethge, Inken Hilgendorf, Andreas Hochhaus, Geoffroy Andrieux, Melanie Börries, Hauke Busch, John Magenau, Pavan Reddy, Myriam Labopin, Joseph H Antin, Andrea S Henden, Geoffrey R Hill, Glen A Kennedy, Merav Bar, Anita Sarma, Donal McLornan, Ghulam Mufti, Betul Oran, Katayoun Rezvani, Omid Sha, Robert S Negrin, Arnon Nagler, Marco Prinz, Andreas Burchert, Andreas Neubauer, Dietrich Beelen, Andreas Mackensen, Nikolas von Bubnoff, Wolfgang Herr, Burkhard Becher, Gerard Socié, Michael A Caligiuri, Eliana Ruggiero, Chiara Bonini, Georg Häcker, Justus Duyster, Jürgen Finke, Erika Pearce, Bruce R Blazar, Robert Zeiser
Individuals with acute myeloid leukemia (AML) harboring an internal tandem duplication (ITD) in the gene encoding Fms-related tyrosine kinase 3 (FLT3) who relapse after allogeneic hematopoietic cell transplantation (allo-HCT) have a 1-year survival rate below 20%. We observed that sorafenib, a multitargeted tyrosine kinase inhibitor, increased IL-15 production by FLT3-ITD+ leukemia cells. This synergized with the allogeneic CD8+ T cell response, leading to long-term survival in six mouse models of FLT3-ITD+ AML...
February 12, 2018: Nature Medicine
https://www.readbyqxmd.com/read/29427040/novel-epigenetic-markers-for-gastric-cancer-risk-stratification-in-individuals-after-helicobacter-pylori-eradication
#7
Masahiro Maeda, Satoshi Yamashita, Taichi Shimazu, Naoko Iida, Hideyuki Takeshima, Takeshi Nakajima, Ichiro Oda, Sohachi Nanjo, Chika Kusano, Akiko Mori, Hiroshi Moro, Harumi Yamada, Shoichiro Tsugane, Toshiro Sugiyama, Yoshiharu Sakai, Toshikazu Ushijima
BACKGROUND: The risk stratification of healthy individuals after Helicobacter pylori eradication is an urgent issue. The assessment of aberrant DNA methylation accumulated in gastric tissues with normal appearance, which can reflect overall epigenomic damage, is a promising strategy. We aimed to establish novel epigenetic cancer risk markers for H. pylori-eradicated individuals. METHODS: Gastric mucosa was collected from eight healthy volunteers without H. pylori infection (G1), 75 healthy individuals with gastric atrophy (G2), and 94 gastric cancer patients (G3) after H...
February 9, 2018: Gastric Cancer
https://www.readbyqxmd.com/read/29423758/impact-of-pre-transplantation-minimal-residual-disease-determined-by-multiparameter-flow-cytometry-on-the-outcome-of-aml-patients-with-flt3-itd-after-allogeneic-stem-cell-transplantation
#8
Xiaosu Zhao, Zhidong Wang, Guorui Ruan, Yanrong Liu, Yu Wang, Xiaohui Zhang, Lanping Xu, Xiaojun Huang, Yingjun Chang
In this study, using multiparameter flow cytometry (FCM), we investigate the impact of minimal residual disease prior to transplantation (pre-MRD) on the transplant outcomes of AML patients with fms-related tyrosine kinase 3 (FLT3)-internal tandem duplication (ITD) mutation. A total of 20 patients who received HLA-matched sibling donor transplantation (MSDT) and 63 patients who received unmanipulated haploidentical hematopoietic stem cell transplantation (haplo-HSCT) were enrolled. Patients were classified into four groups based on the status of pre-FCM: group 1 with positive pre-FCM before MSDT, group 2 with negative pre-FCM before MSDT, group 3 with positive pre-FCM before haplo-HSCT, and group 4 with positive pre-FCM before haplo-HSCT...
February 8, 2018: Annals of Hematology
https://www.readbyqxmd.com/read/29416774/flow-cytometric-characterization-of-acute-leukemia-reveals-a-distinctive-blast-gate-of-murine-t-lymphoblastic-leukemia-lymphoma
#9
Zengkai Pan, Min Yang, Kezhi Huang, Guntram Büsche, Silke Glage, Arnold Ganser, Zhixiong Li
Immunophenotypic analysis using multiparameter flow cytometry is an indispensable tool for diagnosis and management of acute leukemia. Mouse models have been widely used for medical research for more than 100 years and are indispensable for leukemia research. However, immunophenotypic analysis of murine leukemia was not always performed in published studies, and blast gating for isolation of blasts was shown only in very few studies. No systemic characterization of all types of murine acute leukemia in large cohorts by flow cytometry has been reported...
January 5, 2018: Oncotarget
https://www.readbyqxmd.com/read/29416667/discovery-of-a-flt3-inhibitor-ldd1937-as-an-anti-leukemic-agent-for-acute-myeloid-leukemia
#10
Hyo Jeong Lee, Jungeun Lee, Pyeonghwa Jeong, Jungil Choi, Juhwa Baek, Su Jin Ahn, Yeongyu Moon, Jeong Doo Heo, Young Hee Choi, Young-Won Chin, Yong-Chul Kim, Sun-Young Han
FMS-like receptor tyrosine kinase-3 (FLT3) belongs to the family of receptor tyrosine kinase (RTK), and the FLT3 mutation is observed in 1/3 of all acute myeloid leukemia (AML) patients. Potential FLT3 inhibitors have been investigated as potential therapeutic agents of AML. In this study, we identified a potent FLT3 inhibitor LDD1937 containing an indirubin skeleton. The potent inhibitory activity of LDD1937 against FLT3 was shown with an in vitro kinase assay (IC 50 = 3 nM). The LDD1937 compound selectively inhibited the growth of MV-4-11 cells (GI 50 = 1 nM) and induced apoptotic cell death...
January 2, 2018: Oncotarget
https://www.readbyqxmd.com/read/29409989/combined-inhibition-of-pi3k%C3%AE-and-flt3-signaling-exerts-synergistic-antitumor-activity-and-overcomes-acquired-drug-resistance-in-flt3-activated-acute-myeloid-leukemia
#11
Ye He, Liping Sun, Yongping Xu, Li Fu, Yun Li, Xubin Bao, Haoyu Fu, Chengying Xie, Liguang Lou
PI3Kδ and FLT3 are frequently activated in acute myeloid leukemia (AML) and have been implicated as potential therapeutic targets. In this report, we demonstrate that combined inhibition of PI3Kδ and FLT3 exerts synergistic antitumor activity in FLT3-activated AML. Synergistic antiproliferative effects were observed in FLT3-activated MV-4-11 and EOL-1 AML cell lines, but not in FLT3-independent RS4;11 and HEL cells, as demonstrated by both pharmacological inhibition and silencing of PI3Kδ/FLT3. Combined treatment with PI3Kδ and FLT3 inhibitors more effectively inhibited AKT and ERK phosphorylation, and induced apoptosis more efficiently than either agent alone...
February 6, 2018: Cancer Letters
https://www.readbyqxmd.com/read/29408852/high-evi1-expression-predicts-poor-outcomes-in-adult-acute-myeloid-leukemia-patients-with-intermediate-cytogenetic-risk-receiving-chemotherapy
#12
Ya-Zhen Qin, Ting Zhao, Hong-Hu Zhu, Jing Wang, Jin-Song Jia, Yue-Yun Lai, Xiao-Su Zhao, Hong-Xia Shi, Yan-Rong Liu, Hao Jiang, Xiao-Jun Huang, Qian Jiang
BACKGROUND Acute myeloid leukemia with intermediate cytogenetic risk (ICR-AML) needs to be stratified. The abnormal gene expression might be prognostic, and its cutoff value for patient grouping is pivotal. MATERIAL AND METHODS Ecotropic viral integration site 1 (EVI1) transcripts were assessed in 191 adult ICR-AML patients at diagnosis who received chemotherapy only. MLL-PTD, WT1 transcript levels, FLT3-ITD, and NPM1 mutations were simultaneously evaluated, and 27 normal bone marrow samples were tested to define normal threshold...
February 6, 2018: Medical Science Monitor: International Medical Journal of Experimental and Clinical Research
https://www.readbyqxmd.com/read/29403310/the-role-of-brigatinib-in-crizotinib-resistant-non-small-cell-lung-cancer
#13
REVIEW
Laura Mezquita, David Planchard
Despite the advances in new targeted therapies in ALK positive population, most patients progress under ALK inhibitors within first 2 years; being the brain the most frequent site of relapse. ALK mutations, in ~30% of patients, are the main known mechanism of resistance. Classically, second-generation ALK inhibitors have been the standard of care in the crizotinib-resistant population; however, each ALK inhibitor has a different spectrum of sensitivity to ALK mutations, complicating the optimal treatment strategy for the resistant population...
2018: Cancer Management and Research
https://www.readbyqxmd.com/read/29403082/a-reevaluation-of-erythroid-predominance-in-acute-myeloid-leukemia-using-the-updated-who-2016-criteria
#14
Elizabeth Margolskee, Geoff Mikita, Bryan Rea, Adam Bagg, Zhuang Zuo, Yi Sun, Maitrayee Goswami, Sa A Wang, Jean Oak, Daniel A Arber, M Brandon Allen, Tracy I George, Heesun J Rogers, Eric Hsi, Robert P Hasserjian, Attilio Orazi
The 2016 WHO update changed the diagnostic criteria for myeloid neoplasms with erythroid predominance, limiting the diagnosis of acute myeloid leukemia to cases with ≥20% blasts in the bone marrow or peripheral blood. Although acute myeloid leukemia with ≥50% erythroid cells has historically been presumed to represent acute myeloid leukemia with myelodysplasia-related changes, this hypothesis has never been systematically examined. We sought to investigate the clinicopathologic, cytogenetic, and molecular features of acute myeloid leukemia with erythroid predominance to subclassify cases as defined by the 2016 WHO...
February 5, 2018: Modern Pathology: An Official Journal of the United States and Canadian Academy of Pathology, Inc
https://www.readbyqxmd.com/read/29398797/prevalence-and-clinical-significance-of-flt3-and-npm1-mutations-in-acute-myeloid-leukaemia-patients-of-assam-india
#15
Jina Bhattacharyya, Sukanta Nath, Kandarpa Kumar Saikia, Renu Saxena, Sudha Sazawal, Manash Pratim Barman, Dushyant Kumar
Acute Myeloid Leukaemia (AML) is one of the common forms of haematological malignancy in adults. We analysed the prevalence and clinical significance of FMS-like tyrosine kinase 3 (FLT3) and Nucleophosmin 1 (NPM1) mutations in AML patients of North East India. Co-prevalence and clinical significance of three recurrent chromosomal translocations namely t(15; 17), t(8; 21), t(16; 16) and expression of epidermal growth factor receptor (EGFR), flow markers were also documented and co-related with disease progress...
January 2018: Indian Journal of Hematology & Blood Transfusion
https://www.readbyqxmd.com/read/29386373/allogeneic-stem-cell-transplantation-for-flt3-mutated-acute-myeloid-leukemia-in-first-complete-remission-does-age-really-matter
#16
EDITORIAL
Stefan O Ciurea
No abstract text is available yet for this article.
February 2018: Haematologica
https://www.readbyqxmd.com/read/29384595/mll-rearranged-acute-myeloid-leukemia-influence-of-the-genetic-partner-in-allo-hsct-response-and-prognostic-factor-of%C3%A2-mll%C3%A2-3-region-mrna-expression
#17
Sergio Burillo-Sanz, Rosario M Morales-Camacho, Teresa Caballero-Velázquez, Estrella Carrillo, Javier Sánchez, Olga Pérez-López, Inmaculada Pérez de Soto, José González Campos, Concepción Prats-Martín, Ricardo Bernal, M Teresa Vargas
OBJECTIVE: MLL gene is involved in more than 80 known genetic fusions in acute leukemia. To study the relevance of MLL partner gene and selected gene's expression, in this work we have studied a cohort of 20 MLL-rearranged acute myeloid leukemia (AML). METHODS: 20 MLL rearranged AML patients along with a control cohort of 138 AML patients are included in this work. By RT-PCR and sequencing, MLL genetic fusion was characterized, and relative gene expression quantification was carried out for EVI1, MEIS1, MLL-3', RUNX1, SETBP1, HOXA5 and FLT3 genes...
January 31, 2018: European Journal of Haematology
https://www.readbyqxmd.com/read/29383835/flt3-itd-positive-acute-myeloid-leukemia-a-retrospective-analysis-of-the-role-of-allogeneic-transplant-and-allelic-ratio-in-patient-management
#18
Emma Taylor, Kirk Morris, Marc Ellis, Paula Marlton, Ketan Baveshi, Joseph Clarey, Ian Irving, Tara Cochrane, Glen Kennedy
AIM: FMS-like tyrosine kinase 3-internal tandem duplication (FLT3-ITD) positive AML is associated with increased relapse risk and reduced overall survival (OS) compared to non-FLT3-mutated AML. The aim of this study was to evaluate the impact of allelic ratio and allogeneic transplant on outcomes in FLT3-ITD+ AML. METHODS: A retrospective study across five centers in Queensland, Australia, was conducted to examine survival outcomes and impact of FLT3-ITD allelic ratio and allograft...
January 31, 2018: Asia-Pacific Journal of Clinical Oncology
https://www.readbyqxmd.com/read/29374185/synergistic-effect-of-a-novel-autophagy-inhibitor-and-quizartinib-enhances-cancer-cell-death
#19
Amanda Tomie Ouchida, Yingbo Li, Jiefei Geng, Ayaz Najafov, Dimitry Ofengeim, Xiaoxiao Sun, Qiang Yu, Junying Yuan
Drug combinations have been increasingly applied in chemotherapy as a strategy to enhance the efficacy of anti-cancer treatment. The appropriate drug combinations may achieve synergistic effects beyond monotherapies alone. AC220 (Quizartinib), an FLT3 receptor tyrosine kinase inhibitor, developed for the treatment of AML, has been tested in phase II human clinical trials. However, AC220 as a monotherapy is not efficacious enough. In this study, we performed a small-molecule screening of 12 640 compounds in order to find a compound that increase the AC220 efficacy in chemotherapy...
January 26, 2018: Cell Death & Disease
https://www.readbyqxmd.com/read/29372308/internal-tandem-duplication-mutations-in-the-tyrosine-kinase-domain-of-flt3-display-a-higher-oncogenic-potential-than-the-activation-loop-d835y-mutation
#20
Alissa Marhäll, Florian Heidel, Thomas Fischer, Lars Rönnstrand
Acute myeloid leukemia (AML) remains the most common form of acute leukemia among adults and accounts for a large number of leukemia-related deaths. Mutations in FMS-like tyrosine kinase 3 (FLT3) is one of the most prevalent findings in this heterogeneous disease. The major types of mutations in FLT3 can be categorized as internal tandem duplications (ITD) and point mutations. Recent studies suggest that ITDs not only occur in the juxtamembrane region as originally described, but also in the kinase domain. Although the juxtamembrane ITDs have been well characterized, the tyrosine kinase domain ITDs have not yet been thoroughly studied due to their recent discovery...
January 25, 2018: Annals of Hematology
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