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Flt3-itd

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https://www.readbyqxmd.com/read/29786546/flt3-itd-compared-with-dnmt3a-r882-mutation-is-a-more-powerful-independent-inferior-prognostic-factor-in-adult-aml-patients-after-allogeneic-hematopoietic-stem-cell-transplantation-a-retrospective-cohort-study
#1
Majid Teremmahi Ardestani, Ahmad Kazemi, Bahram Chahardouli, Saeed Mohammadi, Mohsen Nikbakht, Shahrbano Rostami, Mahdi Jalili, Mohammad Vaezi, Kamran Alimoghaddam, Ardeshir Ghavamzadeh
OBJECTIVE: To identify DNMT3A exon 23 mutations and their prognostic impact in the presence of FLT3-ITD and NPM1 mutations in acute myeloid leukemia (AML) patients treated with Allo-HSCT. MATERIALS AND METHODS: This study analyzed128 adult AML patients referred to the Hematology-Oncology & Stem Cell Research Center of Shariati hospital. FLT3-ITD and NPM1 mutations were detected using fragment analysis. For DNMT3A exon 23 mutation analysis, we used Sanger sequencing...
May 22, 2018: Turkish Journal of Haematology: Official Journal of Turkish Society of Haematology
https://www.readbyqxmd.com/read/29784639/tyrosine-kinase-inhibitor-induced-defects-in-dna-repair-sensitize-flt3-itd-positive-leukemia-cells-to-parp1-inhibitors
#2
Silvia Maifrede, Margaret Nieborowska-Skorska, Katherine Sullivan, Yashodhara Dasgupta, Paulina Podszywalow-Bartnicka, Bac Viet Le, Martyna Solecka, Zhaorui Lian, Elizaveta A Belyaeva, Alina Nersesyan, Marcin M Machnicki, Monika Toma, Nicolas Chatain, Malgorzata Rydzanicz, Huaqing Zhao, Jaroslav Jelinek, Katarzyna Piwocka, Tomasz Sliwinski, Tomasz Stoklosa, Rafal Ploski, Thomas Fischer, Stephen M Sykes, Steffen Koschmieder, Lars Bullinger, Peter Valent, Mariusz Wasik, Jian Huang, Tomasz Skorski
Mutations in the FMS-like tyrosine-kinase 3 (FLT3) such as internal tandem duplications (ITD) can be found in up to 23% of patients with acute myeloid leukemia (AML) and confer a poor prognosis. Current treatment options for FLT3(ITD)-positive AMLs include genotoxic therapy and FLT3 inhibitors (FLT3i), which are rarely curative. PARP1 inhibitors (PARP1i) have been successfully applied to induce synthetic lethality in tumors harboring BRCA1/2 mutations and displaying homologous recombination (HR) deficiency...
May 21, 2018: Blood
https://www.readbyqxmd.com/read/29773106/-expression-and-purification-of-flt3-and-flt3-itd-mutated-proteins-in-hek293t-cells
#3
Fan Yang, Jiahui Du, Jie Wu, Puyu Yuan, Qian Su, Rong Han, Qiaocheng Qiu, Shengli Xue, Songbai Liu, Zhongwen Sun
Objective To construct the eukaryotic expression vectors of human fms related tyrosine kinase 3 (FLT3) gene and FLT3-internal tandem duplication (FLT3-ITD) mutants and purify the native proteins through immunoprecipitation from HEK293T cell lysates. Methods The cDNA fragments of FLT3wt and FLT3-ITD were amplified from bone marrow cells of healthy individuals and FLT3-ITD-mutated acute myeloid leukemia (AML) patients with specific primers, and the PCR products were cloned in CD530A-T2A-GFP expression vectors...
March 2018: Xi Bao Yu Fen Zi Mian Yi Xue za Zhi, Chinese Journal of Cellular and Molecular Immunology
https://www.readbyqxmd.com/read/29748445/grp94-rewires-and-buffers-the-flt3-itd-signaling-network-and-promotes-survival-of-acute-myeloid-leukemic-stem-cells
#4
Beibei Zhang, Pilar Ayuda Durán, Laure Piechaczyk, Yngvar Fløisand, Mireia Mayoral Safont Safont, Ida Tveit Karlsen, Zina Fandalyuk, Dagim Tadele, Pepijn van Mierlo, Alexander D Rowe, Joseph M Robertson, Bjørn Tore Gjertsen, Emmet McCormack, Jorrit M Enserink
Internal tandem duplications in the tyrosine kinase receptor FLT3 (FLT3-ITD) are among the most common lesions in acute myeloid leukemia and there exists a need for new forms of treatment. Using ex vivo drug sensitivity screening, we found that FLT3-ITD+ patient cells are particularly sensitive to HSP90 inhibitors. While it is well known that HSP90 is important for FLT3-ITD stability, we found that HSP90 family members play a much more complex role in FLT3-ITD signaling than previously appreciated. First, we found that FLT3-ITD activates the unfolded protein response, leading to increased expression of GRP94/HSP90B1...
May 10, 2018: Haematologica
https://www.readbyqxmd.com/read/29724897/targeting-hsp90-dimerization-via-the-c-terminus-is-effective-in-imatinib-resistant-cml-and-lacks-heat-shock-response
#5
Sanil Bhatia, Daniela Diedrich, Benedikt Frieg, Heinz Ahlert, Stefan Stein, Bertan Bopp, Franziska Lang, Tao Zang, Tobias Kröger, Thomas Ernst, Gesine Kögler, Andreas Krieg, Steffen Lüdeke, Hana Kunkel, Ana J Rodrigues Moita, Matthias U Kassack, Viktoria Marquardt, Friederike V Opitz, Marina Oldenburg, Marc Remke, Florian Babor, Manuel Grez, Andreas Hochhaus, Arndt Borkhardt, Georg Groth, Luitgard Nagel-Steger, Joachim Jose, Thomas Kurz, Holger Gohlke, Finn K Hansen, Julia Hauer
Heat shock protein 90 (HSP90) stabilizes many client proteins including BCR-ABL1 oncoprotein. BCR-ABL1 is the hallmark of CML in which treatment-free remission (TFR) is limited with clinical and economic consequences. Thus, there is an urgent need for novel therapeutics, which synergize with current treatment approaches. Several inhibitors targeting the N-terminal domain (NTD) of HSP90 are under investigation; however, side effects such as induction of heat shock response (HSR) and toxicity have so far precluded their FDA approval...
May 3, 2018: Blood
https://www.readbyqxmd.com/read/29723350/clinical-and-pathological-features-of-myeloid-leukemia-cutis
#6
Li Li, Yanan Wang, Christine Guo Lian, Nina Hu, Hongzhong Jin, Yuehua Liu
BACKGROUND: Myeloid leukemia cutis is the terminology used for cutaneous manifestations of myeloid leukemia. OBJECTIVE: The purpose of this study was to study the clinical, histopathological and immunohistochemical features of myeloid leukemia cutis. METHODS: This was a retrospective study of clinical and pathological features of 10 patients with myeloid leukemia cutis. RESULTS: One patient developed skin lesions before the onset of leukemia, seven patients developed skin infiltration within 4-72 months after the onset of leukemia, and two patients developed skin lesions and systemic leukemia simultaneously...
March 2018: Anais Brasileiros de Dermatologia
https://www.readbyqxmd.com/read/29721667/the-influence-of-mutational-status-and-biological-characteristics-of-acute-myeloid-leukemia-on-xenotransplantation-outcomes-in-nod-scid-gamma-mice
#7
Martin Culen, Zdenka Kosarova, Ivana Jeziskova, Adam Folta, Jana Chovancova, Tomas Loja, Nikola Tom, Vojtech Bystry, Veronika Janeckova, Dana Dvorakova, Jiri Mayer, Zdenek Racil
PURPOSE: This study aimed at analyzing the association of gene mutations and other acute myeloid leukemia (AML) characteristics with engraftment outcomes in immunodeficient mice and to select the engraftment outcomes that best reflect patient survival. METHODS: Mutations in 19 genes as well as leukemia- and patient-related characteristics were analyzed for a group of 47 de novo AML samples with respect to three engraftment outcomes: engraftment ability, engraftment intensity (percentage of hCD45+ cells) and engraftment latency...
May 2, 2018: Journal of Cancer Research and Clinical Oncology
https://www.readbyqxmd.com/read/29720585/de-novo-activating-mutations-drive-clonal-evolution-and-enhance-clonal-fitness-in-kmt2a-rearranged-leukemia
#8
Axel Hyrenius-Wittsten, Mattias Pilheden, Helena Sturesson, Jenny Hansson, Michael P Walsh, Guangchun Song, Julhash U Kazi, Jian Liu, Ramprasad Ramakrishan, Cristian Garcia-Ruiz, Stephanie Nance, Pankaj Gupta, Jinghui Zhang, Lars Rönnstrand, Anne Hultquist, James R Downing, Karin Lindkvist-Petersson, Kajsa Paulsson, Marcus Järås, Tanja A Gruber, Jing Ma, Anna K Hagström-Andersson
Activating signaling mutations are common in acute leukemia with KMT2A (previously MLL) rearrangements (KMT2A-R). These mutations are often subclonal and their biological impact remains unclear. Using a retroviral acute myeloid mouse leukemia model, we demonstrate that FLT3 ITD , FLT3 N676K , and NRAS G12D accelerate KMT2A-MLLT3 leukemia onset. Further, also subclonal FLT3 N676K mutations accelerate disease, possibly by providing stimulatory factors. Herein, we show that one such factor, MIF, promotes survival of mouse KMT2A-MLLT3 leukemia initiating cells...
May 2, 2018: Nature Communications
https://www.readbyqxmd.com/read/29716633/targeting-flt3-in-acute-myeloid-leukemia-using-ligand-based-chimeric-antigen-receptor-engineered-t-cells
#9
Ying Wang, Yingxi Xu, Saisai Li, Jia Liu, Yanyan Xing, Haiyan Xing, Zheng Tian, Kejing Tang, Qing Rao, Min Wang, Jianxiang Wang
BACKGROUND: Chimeric antigen receptor-engineered T (CAR-T) cells have extraordinary effect in treating lymphoblastic leukemia. However, treatment of acute myeloid leukemia (AML) using CAR-T cells remains limited to date. Leukemogenesis always relates with the abnormalities of cytogenetics, and nearly one third of AML patients have activating mutations in Fms-like tyrosine kinase 3 (FLT3) which reminded poor prognosis. Considering the FLT3 expressed in AML patients' blast cells, it may be a new candidate target for CAR-T therapy to treat FLT3+ AML, especially patients harboring FLT3-ITD mutation...
May 2, 2018: Journal of Hematology & Oncology
https://www.readbyqxmd.com/read/29705536/high-dose-daunorubicin-new-standard-of-care-for-flt3-itd-mutant-aml
#10
EDITORIAL
Eunice S Wang, Kristen O'Dwyer
No abstract text is available yet for this article.
April 23, 2018: Leukemia Research
https://www.readbyqxmd.com/read/29702736/sorafenib-dose-recommendation-in-acute-myeloid-leukemia-based-on-exposure-flt3-relationship
#11
Tao Liu, Vijay Ivaturi, Philip Sabato, Jogarao V S Gobburu, Jacqueline M Greer, John J Wright, B Douglas Smith, Keith W Pratz, Michelle A Rudek
Sorafenib administered at the approved dose continuously is not tolerated long-term in patients with acute myeloid leukemia (AML). The purpose of this study was to optimize the dosing regimen by characterizing the sorafenib exposure-response relationship in patients with AML. A one-compartment model with a transit absorption compartment and enterohepatic recirculation described the exposure. The relationship between sorafenib exposure and target modulation of kinase targets (FMS-like tyrosine kinase 3 (FLT3)-ITD and extracellular signal-regulated kinase (ERK)) were described by an inhibitory maximum effect (Emax ) model...
April 27, 2018: Clinical and Translational Science
https://www.readbyqxmd.com/read/29696374/baalc-and-erg-expression-levels-at-diagnosis-have-no-prognosis-impact-on-acute-myeloid-leukemia-patients-undergoing-allogeneic-hematopoietic-stem-cell-transplantation
#12
Jilei Zhang, Jinlong Shi, Gaoqi Zhang, Xinpei Zhang, Xinrui Yang, Siyuan Yang, Jing Wang, Xiaoyan Ke, Lin Fu
Brain and acute leukemia, cytoplasmic (BAALC) and ETS-related gene (ERG) expression levels are independent prognostic factors for acute myeloid leukemia (AML); however, their prognostic impacts on AML patients undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT) require further investigation. We studied 71 de novo AML patients treated with allo-HSCT and defined low and high expressers according to the median expression levels of BAALC and ERG at diagnosis respectively. High BAALC expression was associated with wild-type NPM1 (P = 0...
April 25, 2018: Annals of Hematology
https://www.readbyqxmd.com/read/29682194/a-novel-dual-pan-pim-flt3-inhibitor-sel24-exhibits-broad-therapeutic-potential-in-acute-myeloid-leukemia
#13
Wojciech Czardybon, Renata Windak, Aniela Gołas, Michał Gałęzowski, Aleksandra Sabiniarz, Izabela Dolata, Magdalena Salwińska, Paweł Guzik, Magdalena Zawadzka, Ewelina Gabor-Worwa, Bożena Winnik, Małgorzata Żurawska, Ewa Kolasińska, Ewelina Wincza, Marta Bugaj, Monika Danielewicz, Eliza Majewska, Milena Mazan, Grzegorz Dubin, Monika Noyszewska-Kania, Ewa Jabłońska, Maciej Szydłowski, Tomasz Sewastianik, Bartosz Puła, Anna Szumera-Ciećkiewicz, Monika Prochorec-Sobieszek, Elżbieta Mądro, Ewa Lech-Marańda, Krzysztof Warzocha, Jerome Tamburini, Przemysław Juszczyński, Krzysztof Brzózka
Fms-like tyrosine kinase 3 internal tandem duplication (FLT3-ITD) is one of the most common genetic lesions in acute myeloid leukemia patients (AML). Although FLT3 tyrosine kinase inhibitors initially exhibit clinical activity, resistance to treatment inevitably occurs within months. PIM kinases are thought to be major drivers of the resistance phenotype and their inhibition in relapsed samples restores cell sensitivity to FLT3 inhibitors. Thus, simultaneous PIM and FLT3 inhibition represents a promising strategy in AML therapy...
March 30, 2018: Oncotarget
https://www.readbyqxmd.com/read/29672049/discovery-of-n-2-4-amino-cyclohexyl-9-cyclopentyl-n-6-4-morpholin-4-ylmethyl-phenyl-9-h-purine-2-6-diamine-as-a-potent-flt3-kinase-inhibitor-for-acute-myeloid-leukemia-with-flt3-mutations
#14
Tomas Gucky, Eva Řezníčková, Tereza Radosova Muchova, Radek Jorda, Zuzana Klejova, Veronika Malinkova, Karel Berka, Vaclav Bazgier, Haresh Ajani, Martin Lepsik, Vladimir Divoky, Vladimir Krystof
FLT3 tyrosine kinase is a potential drug target in acute myeloid leukemia (AML) because patients with FLT3-ITD mutations respond poorly to standard cytotoxic agents and there is a clear link between the disease and the oncogenic properties of FLT3. We present novel 2,6,9-trisubstituted purine derivatives with potent FLT3 inhibitory activity. The lead compound 7d displays nanomolar activity in biochemical assays and selectively blocks proliferation of AML cell lines harboring FLT3-ITD mutations, whereas other transformed and normal human cells are several orders of magnitude less sensitive...
April 19, 2018: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/29669779/rna-based-flt3-itd-allelic-ratio-is-associated-with-outcome-and-ex-vivo-response-to-flt3-inhibitors-in-pediatric-aml
#15
David G J Cucchi, Barbara Denys, Gertjan Kaspers, Jeroen J W M Janssen, Gert Ossenkoppele, Valérie de Haas, C Michel Zwaan, Marry M van den Heuvel-Eibrink, Jan Philippé, Tamás Csikós, Zinia Kwidama, Barbara de Moerloose, Eveline de Bont, Birgit I Lissenberg-Witte, Sonja Zweegman, Femke Verwer, Karl Vandepoele, Gerrit Jan Schuurhuis, Edwin Sonneveld, Jacqueline Cloos
Controversy exists whether internal tandem duplication of FMS-like tyrosine kinase 3 ( FLT3 -ITD) allelic ratio (AR) and/or length of the ITD should be taken into account for risk stratification of pediatric acute myeloid leukemia (AML) and whether it should be measured on RNA or DNA. Moreover, the ITD status may be of relevance for selecting patients eligible for FLT3 inhibitors. Here, we included 172 pediatric AML patients of whom thirty-six (21%) harbored FLT3 -ITD as determined on both RNA and DNA. Although there was a good correlation between both parameters ARspearman =0...
April 18, 2018: Blood
https://www.readbyqxmd.com/read/29665898/-clinical-characteristics-and-prognosis-of-acute-myeloid-leukemia-with-flt3-itd-mutation
#16
Yan Liu, Xiao-Yan Ke, Jing Wang, Ji-Jun Wang, Hong-Mei Jing, Fei Dong
OBJECTIVE: To investigate the clinical characteristics of acute myeloid leukemia(AML) patients with FLT3-ITD(Fms-like tyrosine kinase3, intenal tandem duplication) mutation and their response to treatment. METHODS: Retrospective analysis of 128 newly diagnosed AML (except type M3) patients was performed between January 2014 and July 2017. Patients were divided into FLT3-ITD mutated group and non-mutated group. Mutation detection was carried out by using polymerase chain reaction(PCR) and gene sequencing analysis...
April 2018: Zhongguo Shi Yan Xue Ye Xue za Zhi
https://www.readbyqxmd.com/read/29664232/correlation-of-tet2-snp-rs2454206-with-improved-survival-in-children-with-acute-myeloid-leukemia-featuring-intermediate-risk-cytogenetics
#17
Xingjuan Wang, Xi Chen, Zhenzhen Yang, Hu Dou, Ling Lu, Junqin Bi, Lin Zou, Jie Yu, Liming Bao
Single nucleotide polymorphisms (SNPs) may influence the disease course and outcome of hematologic neoplasms. SNP rs2454206 is common in the TET2 gene, which plays a role in epigenetic regulation of myelopoiesis. Few investigations examined the role of TET2 SNP rs2454206 in acute myeloid leukemia (AML) and none of those studies was performed in Chinese populations. Here, we report the prevalence and clinical relevance of TET2 SNP rs2454206 in 254 Chinese patients with childhood AML. Our data demonstrate that TET2 SNP rs2454206AG/GG is associated with improved overall survival and event-free survival in AML patients with intermediate-risk cytogenetics features...
April 17, 2018: Genes, Chromosomes & Cancer
https://www.readbyqxmd.com/read/29663558/usefulness-of-bcor-gene-mutation-as-a-prognostic-factor-in-acute-myeloid-leukemia-with-intermediate-cytogenetic-prognosis
#18
Kazuki Terada, Hiroki Yamaguchi, Toshimitsu Ueki, Kensuke Usuki, Yutaka Kobayashi, Kenji Tajika, Seiji Gomi, Saiko Kurosawa, Riho Saito, Yutaka Furuta, Keiki Miyadera, Taichiro Tokura, Atushi Marumo, Ikuko Omori, Masahiro Sakaguchi, Yusuke Fujiwara, Shunsuke Yui, Takeshi Ryotokuji, Kunihito Arai, Tomoaki Kitano, Satoshi Wakita, Takahiro Fukuda, Koiti Inokuchi
BCOR gene is a transcription regulatory factor that plays an essential role in normal hematopoiesis. The wider introduction of next-generation sequencing technology has led to reports in recent years of mutations in the BCOR gene in acute myeloid leukemia (AML), but the related clinical characteristics and prognosis are not sufficiently understood. We investigated the clinical characteristics and prognosis of 377 de novo AML cases with BCOR or BCORL1 mutation. BCOR or BCORL1 gene mutations were found in 28 cases (7...
April 16, 2018: Genes, Chromosomes & Cancer
https://www.readbyqxmd.com/read/29644709/optimizing-the-pretransplant-regimen-for-autologous-stem-cell-transplantation-in-acute-myelogenous-leukemia-better-outcomes-with-busulfan-and-melphalan-compared-with-busulfan-and-cyclophosphamide-in-high-risk-patients-autografted-in-first-complete-remission
#19
Norbert Claude Gorin, Myriam Labopin, Didier Blaise, Pierre-Yves Dumas, Thomas Pabst, Silvia Maria Trisolini, William Arcese, Mohamed Houhou, Mohamad Mohty, Arnon Nagler
Autologous stem cell transplantation (ASCT) remains a clinical option to consolidate some adult patients with acute myelogenous leukemia (AML) in first complete remission (CR1). In a small cohort of patients, we have previously shown better outcomes following Busulfan and Melphalan (BUMEL) over Busulfan and Cyclophosphamide (BUCY). To identify the subpopulations that might get the highest benefit with BUMEL, we designed a larger study. All adult patients with primary AML and available cytogenetics, autografted from January 2000 to December 2016 in CR1, were included: 1137 patients received BUCY and 512 BUMEL...
April 12, 2018: American Journal of Hematology
https://www.readbyqxmd.com/read/29643943/-h19-overexpression-promotes-leukemogenesis-and-predicts-unfavorable-prognosis-in-acute-myeloid-leukemia
#20
Ting-Juan Zhang, Jing-Dong Zhou, Wei Zhang, Jiang Lin, Ji-Chun Ma, Xiang-Mei Wen, Qian Yuan, Xi-Xi Li, Zi-Jun Xu, Jun Qian
Background: The long non-coding RNA H19 plays a crucial role in solid tumor initiation and progression. However, the potential role of H19 and its clinical significance in acute myeloid leukemia (AML) remain largely elusive. Methods: H19 expression was detected by qPCR, and clinical significance in AML patients was further analyzed. The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) data for AML were used as validation cohorts. The roles of H19 in cell proliferation and apoptosis were determined by cell proliferation assay and flow cytometry analysis...
2018: Clinical Epigenetics
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