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https://www.readbyqxmd.com/read/28538663/the-cytokine-flt3-ligand-in-normal-and-malignant-hematopoiesis
#1
REVIEW
Panagiotis Tsapogas, Ciaran James Mooney, Geoffrey Brown, Antonius Rolink
The cytokine Fms-like tyrosine kinase 3 ligand (FL) is an important regulator of hematopoiesis. Its receptor, Flt3, is expressed on myeloid, lymphoid and dendritic cell progenitors and is considered an important growth and differentiation factor for several hematopoietic lineages. Activating mutations of Flt3 are frequently found in acute myeloid leukemia (AML) patients and associated with a poor clinical prognosis. In the present review we provide an overview of our current knowledge on the role of FL in the generation of blood cell lineages...
May 24, 2017: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/28533818/a-novel-bcr-abl1-fusion-gene-with-genetic-heterogeneity-indicates-a-good-prognosis-in-a-chronic-myeloid-leukemia-case
#2
Fen Zhou, Runming Jin, Yu Hu, Heng Mei
BACKGROUND: Chronic myelogenous leukemia (CML) is a pluripotent hematopoietic stem cell disorder caused by the fusion of the BCR and ABL1 genes. Quantitative RT-PCR (qRT-PCR) is a routinely performed screening technique to identify BCR-ABL1 fusion genes, but a limitation of this method is its inability to recognize novel fusions that have not been previously characterized. Next-generation sequencing (NGS) is an effective and sensitive detection method for the determination of novel BCR-ABL1 fusion genes as well as previously characterized ones...
2017: Molecular Cytogenetics
https://www.readbyqxmd.com/read/28526740/midostaurin-gets-fda-nod-for-aml
#3
(no author information available yet)
The FDA has approved the small-molecule inhibitor midostaurin in combination with chemotherapy to treat acute myeloid leukemia. It is the first approved drug for the disease that specifically targets FLT3 mutations, which occur in about a quarter of all AML cases and are associated with particularly poor outcomes.
May 19, 2017: Cancer Discovery
https://www.readbyqxmd.com/read/28523099/identification-of-new-flt3-inhibitors-that-potently-inhibit-aml-cell-lines-via-an-azo-click-it-staple-it-approach
#4
Xiaochu Ma, Jie Zhou, Changhao Wang, Brandon Carter-Cooper, Fan Yang, Elizabeth Larocque, Jonathan Fine, Genichiro Tsuji, Gaurav Chopra, Rena G Lapidus, Herman O Sintim
Acute myeloid leukemia (AML) is an aggressive malignancy with only a handful of therapeutic options. About 30% of AML patients harbor mutated FLT3 kinase, and thus, this cancer-driver has become a hotly pursued AML target. Herein we report a new class of FLT3 inhibitors, which potently inhibit the proliferation of acute myeloid leukemia (AML) cells at nanomolar concentrations.
May 11, 2017: ACS Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28522571/flt3-and-flt3-itd-phosphorylate-and-inactivate-the-cyclin-dependent-kinase-inhibitor-p27kip1-in-acute-myeloid-leukemia
#5
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
#6
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
#7
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/28498310/selective-expression-of-flt3-within-the-mouse-hematopoietic-stem-cell-compartment
#8
Ciaran James Mooney, Alan Cunningham, Panagiotis Tsapogas, Kai-Michael Toellner, Geoffrey Brown
The fms-like tyrosine kinase 3 (Flt3) is a cell surface receptor that is expressed by various hematopoietic progenitor cells (HPC) and Flt3-activating mutations are commonly present in acute myeloid and lymphoid leukemias. These findings underscore the importance of Flt3 to steady-state and malignant hematopoiesis. In this study, the expression of Flt3 protein and Flt3 mRNA by single cells within the hematopoietic stem cell (HSC) and HPC bone marrow compartments of C57/BL6 mice was investigated using flow cytometry and the quantitative reverse transcription polymerase chain reaction...
May 12, 2017: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/28496177/targeting-flt3-by-chimeric-antigen-receptor-t-cells-for-the-treatment-of-acute-myeloid-leukemia
#9
L Chen, H Mao, J Zhang, J Chu, S Devine, M A Caligiuri, J Yu
Leukemia accepted article preview online, 12 May 2017. doi:10.1038/leu.2017.147.
May 12, 2017: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
https://www.readbyqxmd.com/read/28490572/heterogeneous-resistance-to-quizartinib-in-acute-myeloid-leukemia-aml-revealed-by-single-cell-analysis
#10
Catherine C Smith, Amy Paguirigan, Grace R Jeschke, Kimberly C Lin, Evan Massi, Theodore Tarver, Chen-Shan Chin, Saurabh Asthana, Adam Olshen, Kevin J Travers, Susana Wang, Mark J Levis, Alexander E Perl, Jerald P Radich, Neil P Shah
Genomic studies have revealed significant branching heterogeneity in cancer. Studies of resistance to tyrosine kinase inhibitor (TKI) therapy have not fully reflected this heterogeneity as resistance in individual patients has been ascribed to largely mutually exclusive "on-target" or "off-target" mechanisms in which tumors either retain dependency on the target oncogene or subvert it through a parallel pathway. Using targeted sequencing from single cells and colonies from patient samples, we demonstrate tremendous clonal diversity in the majority of acute myeloid leukemia (AML) patients with activating FLT3 internal tandem duplication (ITD) mutations at the time of acquired resistance to the FLT3 inhibitor quizartinib...
May 10, 2017: Blood
https://www.readbyqxmd.com/read/28490193/aminoisoquinoline-benzamides-flt3-and-src-family-kinase-inhibitors-potently-inhibit-proliferation-of-acute-myeloid-leukemia-cell-lines
#11
Elizabeth Larocque, N Naganna, Xiaochu Ma, Clement Opoku-Temeng, Brandon Carter-Cooper, Gaurav Chopra, Rena G Lapidus, Herman O Sintim
AIM: Mutated or overexpressed FLT3 drives about 30% of reported acute myeloid leukemia (AML). Currently, FLT3 inhibitors have shown durable clinical responses but a complete remission of AML with FLT3 inhibitors remains elusive due to mutation-driven resistance mechanisms. The development of FLT3 inhibitors that also target other downstream oncogenic kinases may combat the resistance mechanism. RESULTS: 4-substituted aminoisoquinoline benzamides potently inhibit Src-family kinases and FLT3, including secondary mutations, such as FLT3D835...
May 11, 2017: Future Medicinal Chemistry
https://www.readbyqxmd.com/read/28487694/human-bronchial-epithelial-cells-induce-cd141-cd123-dc-sign-flt3-monocytes-that-promote-allogeneic-th17-differentiation
#12
Amiq Gazdhar, Fabian Blank, Valerie Cesson, Alban Lovis, John David Aubert, Romain Lazor, Francois Spertini, Anne Wilson, Katrin Hostettler, Laurent P Nicod, Carolina Obregon
Little is known about monocyte differentiation in the lung mucosal environment and about how the epithelium shapes monocyte function. We studied the role of the soluble component of bronchial epithelial cells (BECs) obtained under basal culture conditions in innate and adaptive monocyte responses. Monocytes cultured in bronchial epithelial cell-conditioned media (BEC-CM) specifically upregulate CD141, CD123, and DC-SIGN surface levels and FLT3 expression, as well as the release of IL-1β, IL-6, and IL-10. BEC-conditioned monocytes stimulate naive T cells to produce IL-17 through IL-1β mechanism and also trigger IL-10 production by memory T cells...
2017: Frontiers in Immunology
https://www.readbyqxmd.com/read/28486748/telomere-length-is-an-independent-prognostic-marker-in-mds-but-not-in-de-novo-aml
#13
Jenna Williams, Nicole H Heppel, Bethan Britt-Compton, Julia W Grimstead, Rhiannon E Jones, Sudhir Tauro, David T Bowen, Steven Knapper, Michael Groves, Robert K Hills, Chris Pepper, Duncan M Baird, Chris Fegan
Telomere dysfunction is implicated in the generation of large-scale genomic rearrangements that drive progression to malignancy. In this study we used high-resolution single telomere length analysis (STELA) to examine the potential role of telomere dysfunction in 80 myelodysplastic syndrome (MDS) and 95 de novo acute myeloid leukaemia (AML) patients. Despite the MDS cohort being older, they had significantly longer telomeres than the AML cohort (P < 0·0001) where telomere length was also significantly shorter in younger AML patients (age <60 years) (P = 0·02) and in FLT3 internal tandem duplication-mutated AML patients (P = 0·03)...
May 9, 2017: British Journal of Haematology
https://www.readbyqxmd.com/read/28484171/current-diagnosis-and-treatment-for-pediatric-acute-myeloid-leukemia
#14
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/28476569/design-and-synthesis-of-a-fluorinated-quinazoline-based-type-ii-trk-inhibitor-as-a-scaffold-for-pet-radiotracer-development
#15
Vadim Bernard-Gauthier, Anne Mahringer, Matthew Vesnaver, Gert Fricker, Ralf Schirrmacher
NTRK1/2/3 fusions have recently been characterized as low incidence oncogenic alterations across various tumor histologies. Tyrosine kinase inhibitors (TKIs) of the tropomyosin receptor kinase family TrkA/B/C (encoded by NTRK1/2/3) are showing promises in the clinic for the treatment of cancer patients whose diseases harbor NTRK tumor drivers. We describe herein the development of [(18)F]QMICF ([(18)F]-(R)-9), a quinazoline-based type-II pan-Trk radiotracer with nanomolar potencies for TrkA/B/C (IC50=85-650nM) and relevant TrkA fusions including TrkA-TPM3 (IC50=162nM)...
April 21, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28476193/molecular-characterization-of-pediatric-acute-myeloid-leukemia-results-of%C3%A2-a-multicentric-study-in-brazil
#16
Francianne Gomes Andrade, Elda Pereira Noronha, Gisele Dallapicola Brisson, Filipe Dos Santos Vicente Bueno, Ingrid Sardou Cezar, Eugênia Terra-Granado, Luiz Claudio Santos Thuler, Maria S Pombo-de-Oliveira
BACKGROUND AND AIMS: The biological characterization of childhood acute myeloid leukemia (c-AML) is an important outcome predictor. In Brazil, very little is known about the frequency of AML subgroups, although c-AML accounts for about 18% of leukemias. We carried out this study to investigate the contribution of type I and II gene mutations in the probability of overall survival (pOS) of c-AML in Brazil. METHODS: Seven hundred and three de novo pediatric AML cases (2000-2015) were assessed throughout a multicentric network study...
November 2016: Archives of Medical Research
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
#17
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
#18
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/28464908/a-phase-i-study-of-lapatinib-in-combination-with-foretinib-a-c-met-axl-and-vascular-endothelial-growth-factor-receptor-inhibitor-in-human-epidermal-growth-factor-receptor-2-her-2-positive-metastatic-breast-cancer
#19
Stephen K Chia, Susan L Ellard, Mihaela Mates, Stephen Welch, Catalin Mihalcioiu, Wilson H Miller, Karen Gelmon, Caroline Lohrisch, Vikaash Kumar, Sara Taylor, Linda Hagerman, Rachel Goodwin, Tao Wang, Shingo Sakashita, Ming S Tsao, Elizabeth Eisenhauer, Penelope Bradbury
BACKGROUND: The mechanisms of resistance to anti-human epidermal growth factor receptor 2 (HER 2) therapies are unclear but may include the tyrosine-protein kinase Met (c-Met), vascular endothelial growth factor (VEGF) and AXL pathways. Foretinib is an inhibitor of c-Met, VEGF receptor 2 (VEGFR-2), platelet-derived growth factor receptor beta (PDGFRB), AXL, Fms-like tyrosine kinase 3 (FLT3), angiopoiten receptor (TIE-2), RET and RON kinases. This phase Ib study sought to establish the associated toxicities, pharmacokinetics (PK) and recommended phase II doses (RP2D) of foretinib and lapatinib in a cohort of HER-2-positive patients with metastatic breast cancer (MBC)...
May 2, 2017: Breast Cancer Research: BCR
https://www.readbyqxmd.com/read/28463465/dendritic-cell-targeting-dna-based-nasal-adjuvants-for-protective-mucosal-immunity-to-streptococcus-pneumoniae
#20
REVIEW
Kosuke Kataoka, Yoshiko Fukuyama, David E Briles, Tatsuro Miyake, Kohtaro Fujihashi
In order to develop safe vaccines for effective mucosal immunity to major pulmonary bacterial infections, one must consider appropriate vaccine antigens (Ags), delivery systems and nontoxic molecular adjuvants. Such vaccine constructs can induce Ag-specific immune responses which provide effective protection from mucosal infections. In particular, it has been shown that adjuvant-based mucosal vaccine preparations are relatively easy to construct by simply mixing the adjuvant with the bacterial Ag, and the resulting vaccine can elicit protective immunity...
May 2, 2017: Microbiology and Immunology
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