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Flt3-itd

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https://www.readbyqxmd.com/read/28522571/flt3-and-flt3-itd-phosphorylate-and-inactivate-the-cyclin-dependent-kinase-inhibitor-p27kip1-in-acute-myeloid-leukemia
#1
Ines Peschel, Silvio R Podmirseg, Martin Taschler, Justus Duyster, Katharina S Götze, Heinz Sill, David Nachbaur, Heidelinde Jäkel, Ludger Hengst
p27Kip1 can prevent cell proliferation by inactivating cyclin-dependent kinases. This function is impaired upon phosphorylation of p27 at tyrosine residue 88. We observed that FLT3 and FLT3-ITD can directly bind and selectively phosphorylate p27 on this residue. Inhibition of FLT3-ITD in cell lines strongly reduced p27 tyrosine 88 phosphorylation and resulted in increased p27 levels and cell cycle arrest. Subsequent analysis revealed the presence of tyrosine 88 phosphorylated p27 in primary patient samples...
May 18, 2017: Haematologica
https://www.readbyqxmd.com/read/28516360/gilteritinib-a-flt3-axl-inhibitor-shows-antileukemic-activity-in-mouse-models-of-flt3-mutated-acute-myeloid-leukemia
#2
Masamichi Mori, Naoki Kaneko, Yoko Ueno, Masaki Yamada, Ruriko Tanaka, Rika Saito, Itsuro Shimada, Kenichi Mori, Sadao Kuromitsu
Advances in the understanding of the molecular basis for acute myeloid leukemia (AML) have generated new potential targets for treatment. Fms-like tyrosine kinase 3 (FLT3) is one of the most frequently mutated genes in AML and mutations in this gene are associated with poor overall survival. AXL plays a role in the activation of FLT3 and has been implicated in the pathogenesis of AML. The studies reported here evaluated the ability of a novel FLT3/AXL inhibitor, gilteritinib, to block mutated FLT3 in cellular and animal models of AML...
May 17, 2017: Investigational New Drugs
https://www.readbyqxmd.com/read/28507466/high-level-of-mir-196b-at-newly-diagnosed-pediatric-acute-myeloid-leukemia-predicts-a-poor-outcome
#3
Lihua Xu, Yang Guo, Wenying Yan, Jiannong Cen, Yuna Niu, Qing Yan, Hailong He, Chien-Shing Chen, Shaoyan Hu
Differential expression of microRNAs (miRNAs) has been implicated in leukemogenesis. We investigate the expression pattern of miR-196b. Using quantitative real-time PCR (qRT-PCR), we detected the expression of miR-196b and its correlated genes (SMC1A/MLH1) in initial pediatric AML. A significant association was observed between overexpression of miR-196b and inferior overall survival of pediatric AML (Log Rank P<0.0001). AML M4/5 subtype, high white blood cell (WBC) count at presentation, MLL rearrangement, or FLT3-ITD mutation at diagnosis and non-remission group after the first induction chemotherapy possessed higher miR-196b expression...
2017: EXCLI journal
https://www.readbyqxmd.com/read/28484171/current-diagnosis-and-treatment-for-pediatric-acute-myeloid-leukemia
#4
Norio Shiba
Acute myeloid leukemia (AML) is a complex disease caused by chromosomal aberrations, mutations, epigenetic modifications, and the deregulated expression of genes, leading to increased myeloid cell proliferation and decreased hematopoietic progenitor cell differentiation. Although most of these aberrations are correlated with prognosis, accurate risk stratification remains a challenge even after incorporating these molecular markers. Currently, some genetic mutations that allow risk stratification have been identified in adult AML, including DNMT3A and IDH1/2...
2017: [Rinshō Ketsueki] the Japanese Journal of Clinical 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
#5
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/28470536/flt3-itd-and-its-current-role-in-acute-myeloid-leukaemia
#6
REVIEW
Francisco Alejandro Lagunas-Rangel, Venice Chávez-Valencia
FMS-like tyrosine kinase 3 (FLT3) is a proto-oncogene involved in crucial steps of haematopoiesis such as proliferation, differentiation and survival. In recent years, FLT3 has been an important marker in different haematological malignancies, highlighting in acute myeloid leukaemia, where FLT3 mutations have been associated with the clinical prognosis, treatment and survival of patients. The most common form of FLT3 mutation is an internal tandem duplication (ITD) that promotes ligand-independent auto-phosphorylation and constitutive activation of the receptor...
June 2017: Medical Oncology
https://www.readbyqxmd.com/read/28456748/reprogramming-acute-myeloid-leukemia-into-sensitivity-for-retinoic-acid-driven-differentiation
#7
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 to use retinoic acid-based therapy also for other subtypes of acute myeloid leukemia (AML). Recently, several studies showed that ATRA may efficiently drive leukemic cells into differentiation and/or apoptosis in a subset of AML patients with a NPM1 mutation, a FLT3-ITD, an IDH1 mutation, and patients overexpressing EVI-1. Since not all patients within these molecular subgroups respond to ATRA and clinical trials that tested ATRA response in non-APL AML patients have been very disappointing, the identification of additional biomarkers may help to identify patients that strongly respond to ATRA-based therapy...
April 26, 2017: Experimental Hematology
https://www.readbyqxmd.com/read/28450419/phosphoproteome-analysis-reveals-differential-mode-of-action-of-sorafenib-in-wildtype-and-mutated-flt3-aml-cells
#8
Catrin Roolf, Nikolaj Dybowski, Anett Sekora, Stefan Mueller, Gudrun Knuebel, Andreas Tebbe, Hugo Murua Escobar, Klaus Godl, Christian Junghanss, Christoph Schaab
Constitutively activating internal tandem duplication (ITD) alterations of the receptor tyrosine kinase FLT3 (Fms-like tyrosine kinase 3) are common in acute myeloid leukemia (AML) and classifies FLT3 as an attractive therapeutic target. So far, applications of FLT3 small molecule inhibitors have been investigated primarily in FLT3-ITD+ patients. Only recently, a prolonged event-free survival has been observed in AML patients who were treated with the multi-kinase inhibitor sorafenib in addition to standard therapy...
April 27, 2017: Molecular & Cellular Proteomics: MCP
https://www.readbyqxmd.com/read/28447422/minimal-residual-disease-in-acute-myelogenous-leukemia
#9
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
#10
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/28432220/mir-155-promotes-flt3-itd-induced-myeloproliferative-disease-through-inhibition-of-the-interferon-response
#11
Jared A Wallace, Dominique A Kagele, Anna M Eiring, Carissa N Kim, Ruozhen Hu, Marah C Runtsch, Margaret Alexander, Thomas B Huffaker, Soh-Hyun Lee, Ami B Patel, Timothy L Mosbruger, Warren Voth, Dinesh S Rao, Rodney R Miles, June L Round, Michael W Deininger, Ryan M O'Connell
FLT3-ITD(+) AML accounts for approximately 25% of all AML cases, and is a subtype that carries a poor prognosis. miR-155 is specifically overexpressed in FLT3-ITD(+) AML compared to FLT3-WT AML, and is critical for the growth of FLT3-ITD(+) AML cells in vitro. However, miR-155's role in regulating FLT3-ITD-mediated disease in vivo remains unclear. In this study, we utilized a genetic mouse model to determine whether miR-155 influences the development of FLT3-ITD-induced myeloproliferative disease. Results indicate that miR-155 promotes FLT3-ITD-induced myeloid expansion in the bone marrow, spleen, and peripheral blood...
April 21, 2017: Blood
https://www.readbyqxmd.com/read/28420723/mitochondrial-bax-determines-the-predisposition-to-apoptosis-in-human-aml
#12
Frank Reichenbach, Cornelius Wiedenmann, Enrico Schalk, Diana Becker, Kathrin Funk, Peter Scholz-Kreisel, Franziska Todt, Denise Wolleschak, Konstanze Dohner, Jens U Marquardt, Florian Heidel, Frank Edlich
Purpose: Cell-to-cell variability in apoptosis signaling contributes to heterogenic responses to cytotoxic stress in clinically heterogeneous neoplasia, such as acute myeloid leukemia (AML). The BCL-2 proteins BAX and BAK can commit mammalian cells to apoptosis and are inhibited by retrotranslocation from the mitochondria into the cytosol. The subcellular localization of BAX and BAK could determine the cellular predisposition to apoptotic death. Experimental design: The relative localization of BAX and BAK was determined by fractionation of AML cell lines and patient samples of a test cohort and a validation cohort...
April 18, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28419965/chidamide-in-flt3-itd-positive-acute-myeloid-leukemia-and-the-synergistic-effect-in-combination-with-cytarabine
#13
Xia Li, Xiao Yan, Wenjian Guo, Xin Huang, Jiansong Huang, Mengxia Yu, Zhixin Ma, Yu Xu, ShuJuan Huang, Chenying Li, Yile Zhou, Jie Jin
Chidamide, a novel histone deacetylase inhibitor (HDACi), has been approved for treatment of T-cell lymphomas in multiple clinical trials. It has been demonstrated that chidamide can inhibit cell cycle, promote apoptosis and induce differentiation in leukemia cells, whereas its effect on acute myeloid leukemia (AML) patients with FLT3-ITD mutation has not been clarified. In this study, we found that chidamide specifically induced G0/G1 arrest and apoptosis in FLT3-ITD positive AML cells in a concentration and time-dependent manner...
June 2017: Biomedicine & Pharmacotherapy, Biomédecine & Pharmacothérapie
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
#14
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...
April 4, 2017: Leukemia Research
https://www.readbyqxmd.com/read/28395440/-prognostic-significance-of-blood-count-at-the-time-of-achieving-morphologic-leukemia-free-state-in-adults-with-acute-myeloid-leukemia
#15
X Ren, T Zhao, J Wang, H H Zhu, H Jiang, J S Jia, S M Yang, B Jiang, D B Wang, X J Huang, Q Jiang
Objective: To explore prognostic significance of blood count at the time of achieving first morphologic leukemia-free state[complete remission (CR, ANC ≥1×10(9)/L and PLT ≥100×10(9)/L) , CR with incomplete PLT recovery (CRp) and CR with incomplete ANC and PLT recovery (CRi) ]in adult patients with de novo acute myeloid leukemia (AML) . Methods: From January 2008 to February 2016, data of consecutive newly-diagnosed AML (non-APL) adults who received continuous chemotherapy in our hospital were analyzed retrospectively...
March 14, 2017: Zhonghua Xue Ye Xue za Zhi, Zhonghua Xueyexue Zazhi
https://www.readbyqxmd.com/read/28390194/stat5-deficiency-decreases-transcriptional-heterogeneity-and-supports-emergence-of-hematopoietic-sub-populations
#16
Zhengqi Wang, Kevin D Bunting
Aging is associated with significant changes in hematopoiesis, including clonal dominance, anemia, myeloid malignancies, and reduced activation of signal transducer and activator of transcription 5 (Stat5). In previous studies, Stat5 deletion surprisingly amplified FLT3/ITD+ myeloid expansion or Myc-driven lymphoid expansion. Here we show that Stat5 deficiency has a strong impact upon transcriptional heterogeneity in single sorted c-Kit+Lin-Sca-1+ (KLS) cells or CD150+CD48- KLS long-term repopulating hematopoietic stem cells (LT-HSC)...
April 4, 2017: Oncotarget
https://www.readbyqxmd.com/read/28373471/continuation-of-a-levonorgestrel-intrauterine-device-during-hematopoietic-stem-cell-transplant-a-case-report
#17
Paula C Brady, Robert J Soiffer, Elizabeth S Ginsburg
BACKGROUND: During treatment of hematologic malignancies in premenopausal women, both menstrual suppression and contraception are crucial. Continuation of hormonal intrauterine devices (IUDs) - widely used and highly effective contraceptives that also decrease menstrual flow - is controversial during hematopoietic stem cell transplants (SCTs) due to infectious and vaginal bleeding concerns. CASE REPORT: A 23-year-old nulligravid female was diagnosed with acute myeloid leukemia (AML, positive for FLT3-ITD, DNMT3A and RUNX1, with normal cytogenetics)...
April 2017: Anticancer Research
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
#18
Jonathan Canaani, Myriam Labopin, Gerard Socié, Anne Nihtinen, Anne Huynh, Jan Cornelissen, Eric Deconinck, Tobias Gedde-Dahl, Edouard Forcade, Patrice Chevallier, Jean Henri 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 EBMT...
March 28, 2017: American Journal of Hematology
https://www.readbyqxmd.com/read/28318150/expression-of-cd4-is-correlated-with-an-unfavorable-prognosis-in-wild-type-npm1-flt3-itd-negative-cytogenetically-normal-adult-acute-myeloid-leukemia
#19
R J Guo, E G Atenafu, A D Schimmer, M D Minden, H Chang
INTRODUCTION: In the cytogenetically normal population of AML (CN-AML), FLT3-ITD-positive and wild-type NPM1 is correlated with a worse outcome, and FLT3-ITD-negative with NPM1-mut is correlated with a better outcome. This leaves a large subpopulation of CN-AML patients without NPM1 or FLT3-ITD mutations with heterogeneous outcomes with overall survivals (OS) ranging from several weeks to years. Therefore, new prognostic markers are needed to better risk stratify this subset of patients...
March 20, 2017: International Journal of Laboratory Hematology
https://www.readbyqxmd.com/read/28318095/clinicopathologic-and-molecular-characterization-of-myeloid-neoplasms-with-isolated-t-6-9-p23-q34
#20
V Visconte, S Shetty, B Przychodzen, C Hirsch, J Bodo, J P Maciejewski, E D Hsi, H J Rogers
INTRODUCTION: The t(6;9)(p23;q34);DEK-NUP214 [t(6;9)] abnormality is found in 0.7-1.8% of patients with acute myeloid leukemia (AML) or myelodysplastic syndromes (MDS). FLT3-ITD mutations are detected in t(6;9) patients. The t(6;9) abnormality is associated with poor outcomes. We studied the clinicopathologic and molecular profiles of patients with AML/MDS carrying t(6;9). METHODS: We collected clinical data of nine patients with AML/MDS with isolated t(6;9) (median age = 41 years; male/female = 4/5) and genotyped DNAs using whole exome, Sanger, and targeted sequencing...
March 20, 2017: International Journal of Laboratory Hematology
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