keyword
MENU ▼
Read by QxMD icon Read
search

Flt3-itd

keyword
https://www.readbyqxmd.com/read/29339551/inhibition-of-flt3-and-pim-kinases-by-ec-70124-exerts-potent-activity-in-preclinical-models-of-acute-myeloid-leukemia
#1
Noelia Puente-Moncada, Paula Costales, Isaac Antolín, Luz Elena Núñez, Patricia Oro, Maria Ana Hermosilla, Jhudit Perez-Escuredo, Nicolas Rios-Lombardia, Ana M Sanchez-Sanchez, Elisa Luño, Carmen Rodriguez, Vanesa Martin, Francisco Moris
Internal tandem duplication (ITD) or tyrosine kinase domain mutations of FLT3 is the most frequent genetic alteration in acute myeloid leukemia (AML) and are associated with poor disease outcome. Despite considerable efforts to develop single-target FLT3 drugs, so far, the most promising clinical response has been achieved using the multikinase inhibitor midostaurin. Here we explore the activity of the indolocarbazole EC-70124, from the same chemical space as midostaurin, in preclinical models of AML, focusing on those bearing FLT3-ITD mutations...
January 16, 2018: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/29330746/risk-stratified-therapy-for-children-with-flt3-itd-positive-acute-myeloid-leukemia-results-from-the-jplsg-aml-05-study
#2
Akira Shimada, Yuka Iijima-Yamashita, Akio Tawa, Daisuke Tomizawa, Miho Yamada, Shiba Norio, Tomoyuki Watanabe, Takashi Taga, Shotaro Iwamoto, Kiminori Terui, Hiroshi Moritake, Akitoshi Kinoshita, Hiroyuki Takahashi, Hideki Nakayama, Katsuyoshi Koh, Hiroaki Goto, Yoshiyuki Kosaka, Akiko Moriya Saito, Nobutaka Kiyokawa, Keizo Horibe, Yusuke Hara, Kentaro Oki, Yasuhide Hayashi, Shiro Tanaka, Souichi Adachi
Acute myeloid leukemia harboring internal tandem duplication of FMS-like tyrosine kinase 3 (AMLFLT3-ITD) is associated with poor prognosis. We evaluated the results of the AML-05 study, in which all AMLFLT3-ITD patients were assigned to receive hematopoietic stem cell transplantation (HSCT) in the first remission (1CR). We also investigated the effects of additional genetic alterations on FLT3-ITD. The 5-year overall survival (OS) and event-free survival (EFS) rates among the 47 AMLFLT3-ITD patients were 42...
January 12, 2018: International Journal of Hematology
https://www.readbyqxmd.com/read/29326119/association-of-mutations-with-morphologic-dysplasia-in-de-novo-acute-myeloid-leukemia-without-2016-who-classification-defined-cytogenetic-abnormalities
#3
Olga K Weinberg, Christopher J Gibson, Traci M Blonquist, Donna Neuberg, Olga Pozdnyakova, Frank Kuo, Benjamin L Ebert, Robert P Hasserjian
Despite improvements in our understanding of the molecular basis of acute myeloid leukemia, the association between genetic mutations with morphologic dysplasia remains unclear. In this study, we evaluated and scored dysplasia in bone marrow specimens from 168 patients with de novo acute myeloid leukemia; none of these patients had 2016 WHO Classification-defined cytogenetic abnormalities. We then performed targeted sequencing of diagnostic bone marrow aspirates for recurrent mutations associated with myeloid malignancies...
January 11, 2018: Haematologica
https://www.readbyqxmd.com/read/29312564/azacitidine-combined-with-the-selective-flt3-kinase-inhibitor-crenolanib-disrupts-stromal-protection-and-inhibits-expansion-of-residual-leukemia-initiating-cells-in-flt3-itd-aml-with-concurrent-epigenetic-mutations
#4
Anne-Kathrin Garz, Saskia Wolf, Sonja Grath, Verena Gaidzik, Stefan Habringer, Binje Vick, Martina Rudelius, Christoph Ziegenhain, Sylvia Herold, Marie-Theresa Weickert, Martha Smets, Christian Peschel, Robert A J Oostendorp, Sebastian Bultmann, Irmela Jeremias, Christian Thiede, Konstanze Döhner, Ulrich Keller, Katharina S Götze
Effectively targeting leukemia-initiating cells (LIC) in FLT3-ITD-mutated acute myeloid leukemia (AML) is crucial for cure. Tyrosine kinase inhibitors (TKI) have limited impact as single agents, failing to eradicate LIC in the bone marrow. Using primary AML samples and a patient-derived xenograft model, we investigated whether combining the FLT3-selective TKI crenolanib with the hypomethylating agent azacitidine (AZA) eliminates FLT3-ITD LIC and whether efficacy of this combination depends on co-existing mutations...
December 12, 2017: Oncotarget
https://www.readbyqxmd.com/read/29310020/genotypic-and-clinical-heterogeneity-within-nccn-favorable-risk-acute-myeloid-leukemia
#5
Stephen A Strickland, Aaron C Shaver, Michael Byrne, Robert D Daber, P Brent Ferrell, David R Head, Sanjay R Mohan, Claudio A Mosse, Tamara K Moyo, Thomas P Stricker, Cindy Vnencak-Jones, Michael R Savona, Adam C Seegmiller
The National Comprehensive Cancer Network (NCCN) defines the following types of acute myeloid leukemia (AML) as favorable-risk: acute promyelocytic leukemia with t(15;17) (APL); AML with core-binding factor (CBF) rearrangements, including t(8;21) and inv(16) or t(16;16) without mutations in KIT (CBF-KITwt); and AML with normal cytogenetics and mutations in NPM1 (NPM1mut); or biallelic mutations in CEBPA (CEBPAmut/mut), without FLT3-ITD. Although these AMLs are categorized as favorable risk by NCCN, clinical experience suggests that there are differences in clinical outcome amongst these cytogenetically and molecularly distinct leukemias...
January 2, 2018: Leukemia Research
https://www.readbyqxmd.com/read/29309772/gene-mutation-patterns-of-chinese-acute-myeloid-leukemia-patients-by-targeted-next-generation-sequencing-and-bioinformatic-analysis
#6
Xiaoyu Han, Wei Li, Na He, Panpan Feng, Yihua Pang, Chunyan Ji, Daoxin Ma
PURPOSES: The conventional risk stratification of acute myeloid leukemia (AML), based on cytogenetics, cannot meet the demand for accurate prognostic evaluations. In recent years, gene mutations are found to be potential markers for more accurate risk stratification, but reports on mutation screening of Chinese AML are limited. We aim to display the mutation patterns of Chinese AML patients, reveal the genotype-phenotype correlation and make a comparison with Caucasians patients. METHODS: Genome DNA from 78 patients' bone marrow were extracted for targeted gene mutation panel by next-generation sequencing (NGS) technology...
January 5, 2018: Clinica Chimica Acta; International Journal of Clinical Chemistry
https://www.readbyqxmd.com/read/29304116/the-sorafenib-anti-relapse-effect-after-allohsct-is-associated-with-heightened-alloreactivity-and-accumulation-of-cd8-pd-1-cd279-lymphocytes-in-marrow
#7
Andrzej Lange, Emilia Jaskula, Janusz Lange, Grzegorz Dworacki, Dorota Nowak, Aleksandra Simiczyjew, Monika Mordak-Domagala, Mariola Sedzimirska
We studied three FLT3 ITD acute myeloid leukemia (AML) patients who relapsed after allogeneic haematopoietic stem cell transplantation (alloHSCT) and received multikinase inhibitor (MKI) sorafenib as part of salvage therapy. MKI was given to block the effect of FLT3 ITD mutation which powers proliferation of blast cells. However, the known facts that sorafenib is more effective in patents post alloHSCT suggested that this MKI can augment the immune system surveillance on leukaemia. In the present study, we investigated in depth the effect of sorafenib on the alloreactivity seen post-transplant including that on leukaemia...
2018: PloS One
https://www.readbyqxmd.com/read/29299123/inhibition-of-sdf-1-induced-migration-of-oncogene-driven-myeloid-leukemia-by-the-l-rna-aptamer-spiegelmer-nox-a12-and-potentiation-of-tyrosine-kinase-inhibition
#8
Ellen L Weisberg, Martin Sattler, Abdel Kareem Azab, Dirk Eulberg, Anna Kruschinski, Paul W Manley, Richard Stone, James D Griffin
Resistance to targeted tyrosine kinase inhibitors (TKI) remains a challenge for the treatment of myeloid leukemias. Following treatment with TKIs, the bone marrow microenvironment has been found to harbor a small pool of surviving leukemic CD34+ progenitor cells. The long-term survival of these leukemic cells has been attributed, at least in part, to the protective effects of bone marrow stroma. We found that the NOX-A12 'Spiegelmer', an L-enantiomeric RNA oligonucleotide that inhibits SDF-1α, showed in vitro and in vivo activity against BCR-ABL- and FLT3-ITD-dependent leukemia cells...
December 15, 2017: Oncotarget
https://www.readbyqxmd.com/read/29296796/co-occurrence-of-flt3-tkd-and-npm1-mutations-defines-a-highly-favorable-prognostic-aml-group
#9
Prajwal Boddu, Hagop Kantarjian, Gautam Borthakur, Tapan Kadia, Naval Daver, Sherry Pierce, Michael Andreeff, Farhad Ravandi, Jorge Cortes, Steven M Kornblau
Although FLT3 internal tandem duplication (ITD) mutations in acute myeloid leukemia (AML) confer an adverse prognosis, co-occurrence with a nucleophosphomin (NPM1) mutation partially improves response and survival outcomes. In contrast, simultaneous NPM1 and FLT3 tyrosine kinase domain (TKD) mutations were reported to improve response over that of an isolated NPM1 mutation in one as yet unverified report. To validate this, we explored the impact of the co-occurrence of FLT3-TKD and NPM1 mutations on clinical outcomes...
August 22, 2017: Blood Advances
https://www.readbyqxmd.com/read/29288910/3q26-evi1-rearrangement-in-myelodysplastic-myeloproliferative-neoplasms-an-early-event-associated-with-a-poor-prognosis
#10
Zhihong Hu, Shimin Hu, Changsheng Ji, Zhenya Tang, Beenu Thakral, Sanam Loghavi, L Jeffrey Medeiros, Wei Wang
3q26.2/EVI1 rearrangements resulting in EVI1 overexpression play an important role in leukemogenesis and are associated with treatment resistance and a poorer prognosis in patients with acute myeloid leukemia, myelodysplastic syndrome, chronic myeloid leukemia and BCR-ABL negative myeloproliferative neoplasms. In this study, we aim to explore the clinicopathological features of myelodysplastic/myeloproliferative (MDS/MPN) neoplasms with 3q26.2/EVI1 rearrangements and determine the potential impact of these cytogenetic abnormalities on treatment response and survival...
December 23, 2017: Leukemia Research
https://www.readbyqxmd.com/read/29286055/midostaurin-for-the-treatment-of-adult-patients-with-newly-diagnosed-acute-myeloid-leukemia-that-is-flt3-mutation-positive
#11
J S Garcia, M E Percival
Midostaurin is a multitargeted tyrosine kinase inhibitor (TKI) that potently inhibits activated fms-related tyrosine kinase 3 (FLT3) in the nanomolar range and other kinases including platelet-derived growth factor receptors α (PDGFR- α) and β (PDGFR- β), cyclin-dependent kinase, proto-oncogene tyrosine-protein kinase Src, tyrosine-protein kinase Fgr, spleen tyrosine kinase (Syk), KIT proto-oncogene receptor tyrosine kinase and the major vascular endothelial growth factor receptor (VEGFR). Activating mutations in FLT3, which is one of the more common acute myeloid leukemia (AML) mutations, particularly those that result in an FLT3-ITD (internal tandem duplication) mutation, confer poor prognosis and represent a therapeutic target...
October 2017: Drugs of Today
https://www.readbyqxmd.com/read/29285262/nuclear-membrane-localised-nox4d-generates-pro-survival-ros-in-flt3-itd-expressing-aml
#12
Jennifer N Moloney, Ashok Kumar Jayavelu, Joanna Stanicka, Sarah L Roche, Rebecca L O'Brien, Sebastian Scholl, Frank-D Böhmer, Thomas G Cotter
Internal tandem duplication of the juxtamembrane domain of FMS-like tyrosine kinase 3 (FLT3-ITD) is the most prevalent genetic aberration present in 20-30% of acute myeloid leukaemia (AML) cases and is associated with a poor prognosis. FLT3-ITD expressing cells express elevated levels of NADPH oxidase 4 (NOX4)-generated pro-survival hydrogen peroxide (H2O2) contributing to increased levels of DNA oxidation and double strand breaks. NOX4 is constitutively active and has been found to have various isoforms expressed at multiple locations within a cell...
December 1, 2017: Oncotarget
https://www.readbyqxmd.com/read/29274134/a-distinct-immunophenotype-identifies-a-subset-of-npm1-mutated-aml-with-tet2-or-idh1-2-mutations-and-improved-outcome
#13
Emily F Mason, Frank C Kuo, Robert P Hasserjian, Adam C Seegmiller, Olga Pozdnyakova
Recent work has identified distinct molecular subgroups of acute myeloid leukemia (AML) with implications for disease classification and prognosis. NPM1 is one of the most common recurrently mutated genes in acute myeloid leukemia (AML). NPM1 mutations often co-occur with FLT3-ITDs and mutations in genes regulating DNA methylation, such as DNMT3A, TET2, and IDH1/2. It remains unclear whether these genetic alterations are associated with distinct immunophenotypic findings or affect prognosis. We identified 133 cases of NPM1-mutated AML and correlated sequencing data with immunophenotypic and clinical findings...
December 23, 2017: American Journal of Hematology
https://www.readbyqxmd.com/read/29251252/the-clinical-significance-of-flt3-itd-mutation-on-the-prognosis-of-adult-acute-promyelocytic-leukemia
#14
Yingchao Fan, Yanan Cao, Xiaosong Bai, Wenfang Zhuang
BACKGROUND AND AIMS: To explore the relationship between FLT3 (encoding Fms related tyrosine kinase 3) internal tandem duplication (ITD) mutations with the prognosis of acute promyelocytic leukemia. The PubMed database, the Cochrane Library, conference proceedings, the EMBASE databases, and references of published trials and review articles were searched. Two reviewers independently assessed the quality of the trials and extracted the data. Odd ratios (ORs) for complete remission (CR) rate after induction therapy, 5-year overall survival (OS), and 5-year disease free survival (DFS) were pooled using the STATA package...
December 18, 2017: Hematology (Amsterdam, Netherlands)
https://www.readbyqxmd.com/read/29242299/allogeneic-stem-cell-transplantation-benefits-for-patients-%C3%A2-60-years-with-acute-myeloid-leukemia-and-flt3-itd-a-study-from-the-acute-leukemia-working-party-alwp-of-the-european-society-of-blood-and-marrow-transplantation-ebmt
#15
Xavier Poiré, Myriam Labopin, Emmanuelle Polge, Jakob Passweg, Charles Craddock, Didier Blaise, Jan J Cornelissen, Liisa Volin, Nigel H Russell, Gérard Socié, Mauricette Michallet, Nathalie Fegueux, Patrice Chevallier, Arne Brecht, Mathilde Hunault-Berger, Mohamad Mohty, Jordi Esteve, Arnon Nagler
Intermediate-risk cytogenetic acute myeloid leukemia with an internal tandem duplication of FLT3 (FLT3-ITD) is associated with a high risk of relapse and is now a standard indication for allogeneic stem cell transplantation. Nevertheless, most studies supporting this strategy have been performed in young patients. To address the benefit of allogeneic transplantation in elderly patients, we selected from the EBMT registry de novo intermediate-risk cytogenetic acute myeloid leukemia harboring FLT3-ITD in patients with an age equal or over the age of 60 years and transplanted from a related or unrelated donor between January 2000 and December 2015...
December 14, 2017: Haematologica
https://www.readbyqxmd.com/read/29227282/hypoxia-induced-upregulation-of-bmx-kinase-mediates-therapeutic-resistance-in-acute-myeloid-leukemia
#16
Jolieke G van Oosterwijk, Daelynn R Buelow, Christina D Drenberg, Aksana Vasilyeva, Lie Li, Lei Shi, Yong-Dong Wang, David Finkelstein, Sheila A Shurtleff, Laura J Janke, Stanley Pounds, Jeffrey E Rubnitz, Hiroto Inaba, Navjotsingh Pabla, Sharyn D Baker
Oncogenic addiction to the Fms-like tyrosine kinase 3 (FLT3) is a hallmark of acute myeloid leukemia (AML) that harbors the FLT3-internal tandem duplication (FLT3-ITD) mutation. While FLT3 inhibitors like sorafenib show initial therapeutic efficacy, resistance rapidly develops through mechanisms that are incompletely understood. Here, we used RNA-Seq-based analysis of patient leukemic cells and found that upregulation of the Tec family kinase BMX occurs during sorafenib resistance. This upregulation was recapitulated in an in vivo murine FLT3-ITD-positive (FLT3-ITD+) model of sorafenib resistance...
December 11, 2017: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/29214689/distinct-factors-determine-the-kinetics-of-disease-relapse-in-adults-transplanted-for-acute-myeloid-leukaemia
#17
C Craddock, J Versluis, M Labopin, G Socie, A Huynh, E Deconinck, L Volin, N Milpied, J H Bourhis, A Rambaldi, P Chevallier, D Blaise, M Manz, E Vellenga, M-C Vekemans, J Maertens, J Passweg, P Vyas, C Schmid, B Löwenberg, G Ossenkoppele, M Mohty, J J Cornelissen, A Nagler
Disease recurrence remains the major cause of death in adults with acute myeloid leukemia (AML) treated using either intensive chemotherapy (IC) or allogenic stem cell transplantation (allo-SCT). The timely delivery of maintenance drug or cellular therapies represent emerging strategies with the potential to reduce relapse after both treatment modalities, but whilst the determinants of overall relapse risk have been extensively characterized the factors determining the timing of disease recurrence have not been characterized...
December 7, 2017: Journal of Internal Medicine
https://www.readbyqxmd.com/read/29212189/quizartinib-ac220-reverses-abcg2-mediated-multidrug-resistance-in-vitro-and-in-vivo-studies
#18
Jun Li, Priyank Kumar, Nagaraju Anreddy, Yun-Kai Zhang, Yi-Jun Wang, Yanglu Chen, Tanaji T Talele, Kanav Gupta, Louis D Trombetta, Zhe-Sheng Chen
Previous reports have shown that some tyrosine kinase inhibitors (TKIs) could inhibit the ATP-binding cassette (ABC) transporters involved in multidrug resistance (MDR). Quizartinib (AC220), a potent class III receptor tyrosine kinase inhibitor (TKI), was synthesized to selectively inhibit FMS-like tyrosine kinase-3 (FLT3), a target in the treatment of acute myeloid leukemia (AML). Quizartinib is currently under clinical trials for FLT3 ITD and wild-type AML and is tested in combination with chemotherapy. While non-toxic to cell lines, quizartinib at 3 μM showed significant reversal effect on wild-type and mutant ABCG2 (R482T)-mediated MDR, and only a moderate reversal effect on mutant ABCG2 (R482G)-mediated MDR...
November 7, 2017: Oncotarget
https://www.readbyqxmd.com/read/29193057/prognostic-utility-of-six-mutated-genes-for-older-patients-with-acute-myeloid-leukemia
#19
Jinghan Wang, Zhixin Ma, Qinrong Wang, Qi Guo, Jiansong Huang, Wenjuan Yu, Huanping Wang, Jingwen Huang, Yang Washington Shao, Suning Chen, Jie Jin
Approximately 50% of older patients with acute myeloid leukemia (AML) do not obtain chromosomal abnormalities as an effective risk-stratification, and present cytogenetically normal AML (CN-AML). In order to develop a reliable prediction model for stratifying the risk of these elderly patients, we conducted a study with a discovery and validation design. As a result, we found the top 6 mutated genes in the discovery cohort of 26 case by the whole exome sequencing, and verified as recurrent mutations in the large cohort of 329 patients by sanger sequencing...
November 29, 2017: International Journal of Cancer. Journal International du Cancer
https://www.readbyqxmd.com/read/29191878/the-target-landscape-of-clinical-kinase-drugs
#20
Susan Klaeger, Stephanie Heinzlmeir, Mathias Wilhelm, Harald Polzer, Binje Vick, Paul-Albert Koenig, Maria Reinecke, Benjamin Ruprecht, Svenja Petzoldt, Chen Meng, Jana Zecha, Katrin Reiter, Huichao Qiao, Dominic Helm, Heiner Koch, Melanie Schoof, Giulia Canevari, Elena Casale, Stefania Re Depaolini, Annette Feuchtinger, Zhixiang Wu, Tobias Schmidt, Lars Rueckert, Wilhelm Becker, Jan Huenges, Anne-Kathrin Garz, Bjoern-Oliver Gohlke, Daniel Paul Zolg, Gian Kayser, Tonu Vooder, Robert Preissner, Hannes Hahne, Neeme Tõnisson, Karl Kramer, Katharina Götze, Florian Bassermann, Judith Schlegl, Hans-Christian Ehrlich, Stephan Aiche, Axel Walch, Philipp A Greif, Sabine Schneider, Eduard Rudolf Felder, Juergen Ruland, Guillaume Médard, Irmela Jeremias, Karsten Spiekermann, Bernhard Kuster
Kinase inhibitors are important cancer therapeutics. Polypharmacology is commonly observed, requiring thorough target deconvolution to understand drug mechanism of action. Using chemical proteomics, we analyzed the target spectrum of 243 clinically evaluated kinase drugs. The data revealed previously unknown targets for established drugs, offered a perspective on the "druggable" kinome, highlighted (non)kinase off-targets, and suggested potential therapeutic applications. Integration of phosphoproteomic data refined drug-affected pathways, identified response markers, and strengthened rationale for combination treatments...
December 1, 2017: Science
keyword
keyword
14401
1
2
Fetch more papers »
Fetching more papers... Fetching...
Read by QxMD. Sign in or create an account to discover new knowledge that matter to you.
Remove bar
Read by QxMD icon Read
×

Search Tips

Use Boolean operators: AND/OR

diabetic AND foot
diabetes OR diabetic

Exclude a word using the 'minus' sign

Virchow -triad

Use Parentheses

water AND (cup OR glass)

Add an asterisk (*) at end of a word to include word stems

Neuro* will search for Neurology, Neuroscientist, Neurological, and so on

Use quotes to search for an exact phrase

"primary prevention of cancer"
(heart or cardiac or cardio*) AND arrest -"American Heart Association"