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Flt3 itd

Benigno C Valdez, Xiaowen Tang, Yang Li, David Murray, Yan Liu, Uday Popat, Richard E Champlin, Borje S Andersson
The combination of DNA alkylating agents busulfan (Bu) and cyclophosphamide is the most commonly used myeloablative pre-transplant conditioning therapy for myeloid leukemias. However, it is associated with significant non-relapse mortality, which prohibits dose-escalation to control relapse. We hypothesized that combining these two drugs with an epigenetic modifier would increase anti-leukemic efficacy without jeopardizing patient safety. A pre-clinical study was performed to determine the synergistic cytotoxicity of Bu, 4-hydroperoxycyclophosphamide (4HC) and the hypomethylating agent decitabine (DAC) in human AML cell lines...
August 10, 2018: Experimental Hematology
Irum Khan, Marianna Halasi, Anand Patel, Rachael Schultz, Nandini Kalakota, Yi-Hua Chen, Nathan Aardsma, Li Liu, John D Crispino, Nadim Mahmud, Olga Frankfurt, Andrei L Gartel
Acute myeloid leukemia (AML) patients with NPM1 mutations demonstrate a superior response to standard chemotherapy treatment. Our previous work has shown that these favorable outcomes are linked to the cytoplasmic relocalization and inactivation of FOXM1 driven by mutated NPM1. Here, we went on to confirm the important role of FOXM1 in increased chemoresistance in AML. A multiinstitution retrospective study was conducted to link FOXM1 expression to clinical outcomes in AML. We establish nuclear FOXM1 as an independent clinical predictor of chemotherapeutic resistance in intermediate-risk AML in a multivariate analysis incorporating standard clinicopathologic risk factors...
August 9, 2018: JCI Insight
Marielle Perry, Sarah Bertoli, Clément Rocher, Sandrine Hayette, Sophie Ducastelle, Fiorenza Barraco, Hélène Labussière-Wallet, Gilles Salles, Christian Recher, Xavier Thomas, Etienne Paubelle
BACKGROUND: Outcome of patients with mutation of the FLT3 tyrosine kinase domain (FLT3-TKD) in acute myeloid leukemia (AML) remains controversial. PATIENTS AND METHODS: Herein, we present a retrospective study of 126 newly diagnosed patients with AML performed in 2 French centers. RESULTS: FLT3-TKD mutations represented 12.7% of patients, whereas FLT3-internal tandem duplication (ITD) mutation was observed in 20.6% of AML cases and 1.6% of patients harbored both anomalies...
June 13, 2018: Clinical Lymphoma, Myeloma & Leukemia
Daisuke Hidaka, Masahiro Onozawa, Junichi Hashiguchi, Naohiro Miyashita, Kohei Kasahara, Shinichi Fujisawa, Eiko Hayase, Kohei Okada, Souichi Shiratori, Hideki Goto, Junichi Sugita, Masao Nakagawa, Daigo Hashimoto, Kaoru Kahata, Tomoyuki Endo, Satoshi Yamamoto, Yutaka Tsutsumi, Yoshihito Haseyama, Takahiro Nagashima, Akio Mori, Shuichi Ota, Hajime Sakai, Toshimichi Ishihara, Kiyotoshi Imai, Takuto Miyagishima, Yasutaka Kakinoki, Mitsutoshi Kurosawa, Hajime Kobayashi, Hiroshi Iwasaki, Chikara Shimizu, Takeshi Kondo, Takanori Teshima
BACKGROUND: The prognostic effect of Wilms tumor 1 (WT1) expression at the diagnosis of acute myelogenous leukemia (AML) has been controversial. The aim of the present study was to determine the correlations of WT1 expression at the diagnosis of AML with established prognostic alterations. PATIENTS AND METHODS: We analyzed diagnostic bone marrow samples from 252 patients. WT1 expression, single nucleotide polymorphism (SNP) in the WT1 gene (rs16754), and Fms-like tyrosine kinase receptor-3 internal tandem duplication (FLT3-ITD) mutation were analyzed for all patients...
July 17, 2018: Clinical Lymphoma, Myeloma & Leukemia
Song-Bai Liu, Hao-Jie Dong, Xie-Bing Bao, Qiao-Cheng Qiu, Hong-Zhi Li, Hong-Jie Shen, Zi-Xuan Ding, Chao Wang, Xiao-Ling Chu, Jing-Qiu Yu, Tao Tao, Zheng Li, Xiao-Wen Tang, Su-Ning Chen, De-Pei Wu, Ling Li, Sheng-Li Xue
No abstract text is available yet for this article.
August 3, 2018: Haematologica
Elodie Pronier, Robert L Bowman, Jihae Ahn, Jacob Glass, Cyriac Kandoth, Tiffany R Merlinsky, Justin T Whitfield, Benjamin H Durham, Antoine Gruet, Amritha Varshini Hanasoge Somasundara, Raajit Rampal, Ari Melnick, Richard P Koche, Barry S Taylor, Ross L Levine
Genetic studies have identified recurrent somatic mutations in Acute Myeloid Leukemia (AML) patients, including in the WT1 (Wilms' tumor 1) gene. The molecular mechanisms by which WT1 mutations contribute to leukemogenesis have not yet been fully elucidated. We investigated the role of Wt1 gene dosage in steady-state and pathologic hematopoiesis. Wt1 heterozygous loss enhanced stem cell self-renewal in an age- dependent manner, which increased stem cell function over time and resulted in age- dependent leukemic transformation...
July 31, 2018: Blood
Katrin Schranz, Max Hubmann, Egor Harin, Sebastian Vosberg, Tobias Herold, Klaus H Metzeler, Maja Rothenberg-Thurley, Hanna Janke, Kathrin Bräundl, Bianka Ksienzyk, Aarif M N Batcha, Sebastian Schaaf, Stephanie Schneider, Stefan K Bohlander, Dennis Görlich, Wolfgang E Berdel, Bernhard J Wörmann, Jan Braess, Stefan Krebs, Wolfgang Hiddemann, Ulrich Mansmann, Karsten Spiekermann, Philipp A Greif
In acute myeloid leukemia (AML), internal tandem duplications (ITDs) of FLT3 are frequent mutations associated with unfavorable prognosis. At diagnosis, the FLT3- ITD status is routinely assessed by fragment analysis, providing information about the length but not the position and sequence of the ITD. To overcome this limitation, we performed cDNA-based high-throughput amplicon sequencing (HTAS) in 250 FLT3- ITD positive AML patients, treated on German AML Cooperative Group (AMLCG) trials. FLT3- ITD status determined by routine diagnostics was confirmed by HTAS in 242 out of 250 patients (97%)...
July 10, 2018: Oncotarget
Maro Ohanian, Guillermo Garcia-Manero, Mark Levis, Elias Jabbour, Naval Daver, Gautam Borthakur, Tapan Kadia, Sherry Pierce, Jan Burger, Mary Ann Richie, Keyur Patel, Michael Andreeff, Zeev Estrov, Jorge Cortes, Hagop Kantarjian, Farhad Ravandi
Based on our previous study of the combination of sorafenib with 5-azacytidine (AZA) in relapsed/refractory patients with FLT3 mutated acute myeloid leukemia (AML), we hypothesized that the combination would be efficacious and well tolerated in untreated patients with FLT3 mutated AML who are unsuitable for standard chemotherapy due to advanced age or lack of fitness. Newly diagnosed patients with untreated FLT3 mutated AML who underwent frontline therapy on two separate protocols of AZA plus sorafenib were analyzed...
July 20, 2018: American Journal of Hematology
Mayu Takami, Kazuhiro Katayama, Kohji Noguchi, Yoshikazu Sugimoto
FMS-like tyrosine kinase 3 (FLT3)-internal tandem duplication (ITD) is a constitutively active mutant of FLT3 and causes 20%-30% of acute myeloid leukemia (AML) cases. FLT3-ITD upregulates the proviral integration site for Moloney murine leukemia virus 1 (PIM-1) expression and promotes the proliferation of AML cells. In this study, we investigated the role of protein kinase C (PKC)-mediated phosphorylation on the expression and function of PIM-1L. Drug screening in leukemia cell lines revealed that sotrastaurin (a PKC inhibitor) suppressed the proliferation of the FLT3-ITD-positive AML cell line MV4-11 but not of K562, HL60, or KG-1a cells, similar to SGI-1776 (a PIM-1/FLT3 inhibitor) and quizartinib (an FLT3 inhibitor)...
July 12, 2018: Biochemical and Biophysical Research Communications
Patrizia Zappasodi, Laura Marbello, Erika Borlenghi, Monica Fumagalli, Massimo Bernardi, Nicola Fracchiolla, Valentina Mancini, Matteo Da Vià, Emanuele Ravano, Elisa Cerqui, Virginia Valeria Ferretti, Barbara Rocca, Celeste Calvello, Mario Cazzola, Carlo Castagnola, Giuseppe Rossi
Favorable acute myeloid leukemia (AML) patients (pts.) demonstrate a relatively good outcome with standard induction; thus, pts. are generally not addressed to allogeneic transplant in first remission. However, it is not clear if also in a real-life setting, the outcome is homogeneous in the different favorable molecular groups and which are the parameters significantly associated to an increased relapse risk, useful to suggest the need of an intensified approach. In order to clarify this point, we collected clinical data on consecutive unselected AML pts...
July 15, 2018: Annals of Hematology
Katja Seipel, Miguel A T Marques, Corinne Sidler, Beatrice U Mueller, Thomas Pabst
Prognosis for FLT3-ITD positive acute myeloid leukemia with high allelic ratio (>0.5) is poor, particularly in relapse, refractory to or unfit for intensive treatment, thus highlighting an unmet need for novel therapeutic approaches. The combined use of compounds targeting both the mutated FLT3 receptor and cellular p53 inhibitors might be a promising treatment option for this poor risk leukemia subset. We therefore assessed MDM2 and FLT3 inhibitors as well as cytotoxic compounds used for conventional induction treatment as single agents and in combination for their ability to induce apoptosis and cell death in leukemic cells...
July 5, 2018: Haematologica
Andrea Kuendgen, Catharina Müller-Thomas, Michael Lauseker, Torsten Haferlach, Petra Urbaniak, Thomas Schroeder, Carolin Brings, Michael Wulfert, Manja Meggendorfer, Barbara Hildebrandt, Beate Betz, Brigitte Royer-Pokora, Norbert Gattermann, Rainer Haas, Ulrich Germing, Katharina S Götze
Azacitidine is the first drug to demonstrate a survival benefit for patients with MDS. However, only half of patients respond and almost all patients eventually relapse. Limited and conflicting data are available on predictive factors influencing response. We analyzed 128 patients from two institutions with MDS or AML treated with azacitidine to identify prognostic indicators. Genetic mutations in ASXL1, RUNX1, DNMT3A, IDH1, IDH2, TET2, TP53, NRAS, KRAS, FLT3, KMT2A-PTD, EZH2, SF3B1, and SRSF2 were assessed by next-generation sequencing...
June 12, 2018: Oncotarget
Zhiheng Cheng, Yifeng Dai, Yifan Pang, Yang Jiao, Hongmian Zhao, Sun Wu, Lingxiu Zhang, Yuan Zhang, Xiufeng Wang, Lihua Wang, Dong Ma, Tong Qin, Ning Hu, Yijie Zhang, Kai Hu, Qingyi Zhang, Jinlong Shi, Lin Fu
BACKGROUND/AIMS: Acute myeloid leukemia (AML) of French-American-British (FAB) subtypes M0 and M1 are both poorly differentiated AML, but their mutational spectrum and molecular characteristics remain unknown. This study aimed to explore the mutational spectrum and prognostic factors of AML-M0 and M1. METHODS: Sixty-five AML patients derived from The Cancer Genome Atlas (TCGA) database were enrolled in this study. Whole-genome sequencing was performed to depict the mutational spectrum of each patient...
2018: Cellular Physiology and Biochemistry
Rui Wang, Ying Li, Ping Gong, Janice Gabrilove, Samuel Waxman, Yongkui Jing
Acute myeloid leukemia (AML) with Fms-related tyrosine kinase 3 internal tandem duplication (FLT3-ITD) mutation is notoriously hard to treat. We identified two drugs that together form an effective combination therapy against FLT3-ITD AML. One of the drugs, Sorafenib, an inhibitor of FLT3-ITD and other kinase activity, produces an impressive but short-lived remission in FLT3-ITD AML patients. The second, arsenic trioxide (ATO), at therapeutically achievable concentrations, reduces the level of FLT3-ITD and Mcl-1 proteins, and induces apoptosis in leukemic cell lines and in primary cells expressing FLT3-ITD...
June 29, 2018: Molecular Cancer Therapeutics
Kinjal Shah, Sausan A Moharram, Julhash U Kazi
The PI3K/mTOR pathway is the second most frequently deregulated pathway in a majority of cancers such as breast cancer, lung cancer, and melanomas as well as leukemia. Mutations in the genes coding for receptor tyrosine kinases (RTKs) and G-protein-coupled receptors (GPCRs) are quite common in all forms of acute leukemia. This can be a major cause of deregulation of the PI3K-mTOR pathway. To understand how cells display resistance to the dual PI3K/mTOR inhibitor, we used a panel of 25 acute leukemia cell lines...
2018: Clinical Epigenetics
Fang Chen, Xue-Jie Jiang, Chang-Xin Yin, Qing-Xiu Zhong, Ling Jiang, Guo-Pan Yu, Jing Sun, Fan-Yi Meng
OBJECTIVE: To explore the influence of FLT3-ITD mutation and ITD length on the overall survival (OS) and relapse free survival(RFS) in patients with non-M3 acute myeloid leukemia. METHODS: Clinical features and therapeutic effect were retrospectively analyzed in 75 AML patients with FLT3-ITD mutation and 76 FLT3-ITD- AML patients with a normal karotype from June 2011 to April 2016. Genomic DNA was amplified by PCR, and FLT3-ITD mutation length was analyzed by DNA sequencing in 40 patients...
June 2018: Zhongguo Shi Yan Xue Ye Xue za Zhi
Yongsheng Xiang, Xiaofen Zhou
OBJECTIVE: To investigate the correlation of octamer-binding transcription factor 4 (OCT4) expression with clinicopathological features and its predictive value for treatment response as well as survival profiles in de novo acute myeloid leukaemia (AML) patients. METHOD: One hundred fifty-two de novo AML patients and 52 non-hematologic malignancy patients were recruited in this prospective cohort study. OCT4 expression was determined in bone marrow sample collected before treatment...
June 27, 2018: Hematology (Amsterdam, Netherlands)
D F Akin, D A Oner, E Kurekci, N Akar
OBJECTIVES: The CCAAT/enhancer-binding protein-alpha (CEBPA) is lineage-specific transcription factor in the hematopoietic system. In this study, we aimed on the clinical features and the prognostic significance associated with CEBPA mutations in 30 pediatric patients with acute leukemia. METHODS: In addition, the association between found variants and mutations of Ten-Eleven-Translocation 2 (TET2), Kirsten rat sarcoma viral oncogene homolog (KRAS), and Casitas B-cell lymphoma (CBL), FLT3 (Fms-Related Tyrosine Kinase), JAK2 (Januse Kinase-2) and Nucleophosmin 1 (NPM1) were analyzed, which are important prognostic risk factors for pediatric acute leukemia patients...
2018: Bratislavské Lekárske Listy
Zoltán Nemes, Krisztina Takács-Novák, Gergely Völgyi, Klara Valko, Szabolcs Béni, Zoltán Horváth, Bálint Szokol, Nóra Breza, Judit Dobos, Csaba Szántai-Kis, Eszter Illyés, Sándor Boros, Robbert Jan Kok, László Őrfi
Acute myeloid leukemia (AML) is the most common type of leukemia in adults. Sunitinib, a multikinase inhibitor, was the first Fms-like tyrosine kinase 3 (FLT3) inhibitor clinically used against AML. Off-target effects are a major concern for multikinase inhibitors. As targeted delivery may reduce such undesired side effects, our goal was to develop novel amino acid substituted derivatives of sunitinib which are potent candidates to be used conjugated with antibodies and peptides. In the current paper we present the synthesis, physicochemical and in vitro characterization of sixty two Fms-like tyrosine kinase 3-internal tandem duplication (FLT3-ITD) mutant kinase inhibitors, bearing amino acid moieties, fit to be conjugated with peptide-based delivery systems via their carboxyl group...
August 1, 2018: Bioorganic & Medicinal Chemistry Letters
Eman Z Kandeel, Ghada El Sayed, Nahla Elsharkawy, Dalia Negm Eldin, Hanan R Nassar, Dalia Ibrahiem, Randa Amin, Marwa Hanafi, Mohamed Khalil, Azza Kamel
BACKGROUND: The significance of FMS-like tyrosine kinase 3 (FLT3)-ITD mutation in acute myeloid leukemia (AML) prognosis has been well established. The aims of this study were to investigate the prognostic impact of the FLT3 protein (CD135) expression and its association with FLT3-ITD mutation, and to identify its role in minimal residual disease. PATIENTS AND METHODS: CD135 was measured by flow cytometry on leukemic blasts of 257 adults with de novo AML. High expression of CD135 ≥ 20% was correlated with clinical, laboratory, and other prognostic factors that influenced treatment outcome...
August 2018: Clinical Lymphoma, Myeloma & Leukemia
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