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Rayapadi G Swetha, Sudha Ramaiah, Anand Anbarasu
Mutations in Fetal Liver Tyrosine Kinase 3 (FLT3) genes are implicated in the constitutive activation and development of Acute Myeloid Leukaemia (AML). They are involved in signalling pathway of autonomous proliferation and block differentiation in leukaemia cells. FLT3 is considered as a promising target for the therapeutic intervention of AML. There are a few missense mutations associated with FLT3 that are found in AML patients. The D835N mutation is the most frequently observed and the aspartic acid in this position acts as a key residue for the receptor activation...
June 2016: Journal of Cellular Biochemistry
Jolanta Krajewska, Tomasz Olczyk, Barbara Jarzab
Cabozantinib (XL-184) is a potent inhibitor of MET, VEGFR 2/KDR, RET and other receptor tyrosine kinases, such as KIT, AXL and FLT3. Its efficacy against MTC has been demonstrated in a prospective, randomized, placebo-controlled study (EXAM). Cabozantinib comparing to placebo significantly prolonged progression free survival both in hereditary and sporadic MTC, 11.2 vs 4.0 months, respectively. Final analysis showed no global differences in overall survival (OS) between cabozantinib and placebo. However, in a subgroup with RET M918T mutation the difference in OS was significant: 44...
2016: Expert Review of Clinical Pharmacology
Yan Beauverd, Donal P McLornan, Claire N Harrison
INTRODUCTION: Myelofibrosis (MF) is a clonal haematological disease associated with recurrent somatic gene mutations (JAK2V617F, MPL, CALR) and constitutive activation of the Janus kinase (JAK)/Signal Transducer and Activator of Transcription pathway. MF is often characterised by debilitating symptoms and JAK inhibitors (JAKIs) have revolutionised available therapeutic options. Ruxolitinib, a JAK1 and 2 inhibitor, is the only currently approved agent. Several other JAKIs are undergoing evaluation in the clinical trial setting and Pacritinib , a novel JAK2 and FLT3 inhibitor, is at an advanced stage of investigation with recent completion of a Phase III trial and another ongoing...
2015: Expert Opinion on Pharmacotherapy
Hong-Guang Xia, Ayaz Najafov, Jiefei Geng, Lorena Galan-Acosta, Xuemei Han, Yuan Guo, Bing Shan, Yaoyang Zhang, Erik Norberg, Tao Zhang, Lifeng Pan, Junli Liu, Jonathan L Coloff, Dimitry Ofengeim, Hong Zhu, Kejia Wu, Yu Cai, John R Yates, Zhengjiang Zhu, Junying Yuan, Helin Vakifahmetoglu-Norberg
Hexokinase II (HK2), a key enzyme involved in glucose metabolism, is regulated by growth factor signaling and is required for initiation and maintenance of tumors. Here we show that metabolic stress triggered by perturbation of receptor tyrosine kinase FLT3 in non-acute myeloid leukemia cells sensitizes cancer cells to autophagy inhibition and leads to excessive activation of chaperone-mediated autophagy (CMA). Our data demonstrate that FLT3 is an important sensor of cellular nutritional state and elucidate the role and molecular mechanism of CMA in metabolic regulation and mediating cancer cell death...
August 31, 2015: Journal of Cell Biology
Giuseppe Pelosi, Alessandra Fabbri, Mauro Papotti, Giulio Rossi, Alberto Cavazza, Luisella Righi, Elena Tamborini, Federica Perrone, Giulio Settanni, Adele Busico, Maria Adele Testi, Patrick Maisonneuve, Filippo De Braud, Marina Garassino, Barbara Valeri, Angelica Sonzogni, Ugo Pastorino
INTRODUCTION: Little is known about genotypic and phenotypic correlations in undifferentiated large-cell carcinoma (LCC) of the lung. METHODS: Thirty LCC were dissected by unsupervised targeted next generation sequencing analysis for 50 cancer-associated oncogenes and tumor suppressor genes. Cell differentiation lineages were unveiled by using thyroid transcription factor-1 (TTF1) for adenocarcinoma (ADC) and p40 for squamous cell carcinoma (SQC), dichotomizing immunohistochemistry (IHC) results for TTF1 as negative or positive (whatever its extent) and for p40 as negative, positive, or focal (if <10% of reactive tumor cells)...
November 2015: Journal of Thoracic Oncology
Hua-Yuan Zhu, Yuan Fu, Wei Wu, Jia-Dai Xu, Ting-Mei Chen, Chun Qiao, Jian-Yong Li, Peng Liu
OBJECTIVE: To investigate the expression of BAG3 gene in acue myeloid leukemia (AML) and its prognostic value. METHODS: Real-time quantitative RT-PCR was used to detect the expression of BAG3 mRNA in 88 previously untreated AML patients. The corelation of BAG3 expression level with clinical characteristics and known prognostic markers of AML was analyzed. RESULTS: In 88 patients with AML, the expression of BAG3 mRNA in NPMI mutated AML patients was obviously lower than that in NPMI unmutated patients (P = 0...
August 2015: Zhongguo Shi Yan Xue Ye Xue za Zhi
Talha Badar, Hagop M Kantarjian, Graciela M Nogueras-Gonzalez, Gautam Borthakur, Guillermo Garcia Manero, Michael Andreeff, Marina Konopleva, Tapan M Kadia, Naval Daver, William G Wierda, Raja Luthra, Keyur Patel, Betul Oran, Richard Champlin, Farhad Ravandi, Jorge E Cortes
AML with FLT3 ITD mutations are associated with poor outcome. We reviewed outcomes of patients with FLT3 ITD mutated AML to investigate trends over time. We analyzed 224 AML patients (excluding patients with core binding factor and acute promyelocytic leukemia) referred to our institution between 2000 and 2014. Patients were divided into five cohorts by era: 2000-2002 (Era 1, n = 19), 2003-2005 (Era 2, n = 41), 2006-2008 (Era 3, n = 53), 2009-2011 (Era 4, n = 55), and 2012-2014 (Era 5, n = 56) to analyze differences in outcome...
November 2015: American Journal of Hematology
Yeonui Kwak, Hanna Cho, Wooyoung Hur, Taebo Sim
Uncontrolled activation of FGFRs induces the progression of various cancers. It was recently reported that FGFR2-activating mutants are implicated in about 12% of endometrial carcinomas. AZD4547, a potent pan-FGFR inhibitor, is currently being evaluated in clinical trials for several FGFR-driven cancers. However, AZD4547 has not been examined yet against FGFR2 mutant-driven endometrial cancers. Thus, we evaluated the activity of AZD4547 against four different endometrial cancer cells, including AN3-CA, MFE296, MFE280, and HEC1A, where all but HEC1A cells express distinctive FGFR2 mutations...
October 2015: Molecular Cancer Therapeutics
Krupa Shah, Sheefa Mirza, Urja Desai, Nayan Jain, Rakesh Rawal
BACKGROUND: The aim of the study was to find a role of Curcumin from natural source to overcome drug resistance as well as to reduce cytotoxicity profile of the drug in Acute Myeloid Leukemia patients. MATERIAL AND METHODS: Primary leukemic cells were obtained from AML patient's bone marrow. These cells were then exposed to different concentration of cytarabine and curcumin to find out IC50 values and also its effect on MDR genes like MDR1, BCRP, LRP and FLT3 by RT-PCR method...
2016: Anti-cancer Agents in Medicinal Chemistry
Jing-Dong Zhou, Dong-Ming Yao, Ying-Ying Zhang, Ji-Chun Ma, Xiang-Mei Wen, Jing Yang, Hong Guo, Qin Chen, Jiang Lin, Jun Qian
Hypermethylation of GPX3 (glutathione peroxidase 3) promoter has been identified in various solid tumors. However, the pattern of GPX3 promoter methylation in acute myeloid leukemia (AML) remains unknown. The current study was intended to investigate the clinical significance of GPX3 promoter methylation in de novo AML patients and further determine its role in regulating GPX3 expression. GPX3 promoter methylation status was detected in 181 de novo AML patients and 44 normal controls by real-time quantitative methylation-specific PCR and bisulfite sequencing PCR...
2015: American Journal of Cancer Research
Ellen Weisberg, Ensar Halilovic, Vesselina G Cooke, Atsushi Nonami, Tao Ren, Takaomi Sanda, Irene Simkin, Jing Yuan, Brandon Antonakos, Louise Barys, Moriko Ito, Richard Stone, Ilene Galinsky, Kristen Cowens, Erik Nelson, Martin Sattler, Sebastien Jeay, Jens U Wuerthner, Sean M McDonough, Marion Wiesmann, James D Griffin
The tumor suppressor p53 is a key regulator of apoptosis and functions upstream in the apoptotic cascade by both indirectly and directly regulating Bcl-2 family proteins. In cells expressing wild-type (WT) p53, the HDM2 protein binds to p53 and blocks its activity. Inhibition of HDM2:p53 interaction activates p53 and causes apoptosis or cell-cycle arrest. Here, we investigated the ability of the novel HDM2 inhibitor CGM097 to potently and selectively kill WT p53-expressing AML cells. The antileukemic effects of CGM097 were studied using cell-based proliferation assays (human AML cell lines, primary AML patient cells, and normal bone marrow samples), apoptosis, and cell-cycle assays, ELISA, immunoblotting, and an AML patient-derived in vivo mouse model...
October 2015: Molecular Cancer Therapeutics
Y Song, J Magenau, Y Li, T Braun, L Chang, D Bixby, D A Hanauer, K A Chughtai, E Gatza, D Couriel, S Goldstein, A Pawarode, P Reddy, M Riwes, J Connelly, A Harris, C Kitko, J Levine, G Yanik, B Parkin, S W Choi
Allogeneic hematopoietic cell transplantation (HCT) has been increasingly used in the setting of FMS-like tyrosine kinase-3 (FLT3)-mutated AML. However, its role in conferring durable relapse-free intervals remains in question. Herein we sought to investigate FLT3 mutational status on transplant outcomes. We conducted a retrospective cohort study of 262 consecutive AML patients who underwent first-time allogeneic HCT (2008-2014), of whom 171 had undergone FLT3-ITD (internal tandem duplication) mutational testing...
April 2016: Bone Marrow Transplantation
Jing-Dong Zhou, Dong-Ming Yao, Ying-Ying Zhang, Ji-Chun Ma, Xiang-Mei Wen, Jing Yang, Hong Guo, Qin Chen, Jiang Lin, Jun Qian
Hypermethylation of GPX3 (glutathione peroxidase 3) promoter has been identified in various solid tumors. However, the pattern of GPX3 promoter methylation in acute myeloid leukemia (AML) remains poorly known. The current study was intended to investigate the clinical significance of GPX3 promoter methylation in de novo AML patients and further determine its role in regulating GPX3 expression. GPX3 promoter methylation status in 181 de novo AML patients and 44 normal controls was detected by real-time quantitative methylation-specific PCR and bisulfite sequencing PCR...
2015: American Journal of Cancer Research
Vivian Cristina Oliveira, Nilmar Silvo Moretti, Leonardo da Silva Augusto, Sergio Schenkman, Mario Mariano, Ana Flavia Popi
Ikaros, a zinc finger transcription factor, is an important regulator of the hematopoietic system. Several studies have suggested the role of Ikaros in the development, maturation, activation and differentiation of lymphocytes. To elucidate this mechanism, it is important to understand how this transcription factor works in the dichotomy of the hematopoietic system, a topic that remains uncertain. Herein, we investigated the role of Ikaros in the control of the lymphomyeloid phenotype of B-1 lymphocytes. We found that Ikaros, as well as its target genes, are expressed in B-1 cells,...
November 2015: Immunobiology
Jean-Emmanuel Bibault, Martin Figeac, Nathalie Hélevaut, Céline Rodriguez, Sabine Quief, Shéhérazade Sebda, Aline Renneville, Olivier Nibourel, Philippe Rousselot, Bérengère Gruson, Hervé Dombret, Sylvie Castaigne, Claude Preudhomme
Minimal Residual Disease (MRD) detection can be used for early intervention in relapse, risk stratification, and treatment guidance. FLT3 ITD is the most common mutation found in AML patients with normal karyotype. We evaluated the feasibility of NGS with high coverage (up to 2.4.10(6) PE fragments) for MRD monitoring on FLT3 ITD. We sequenced 37 adult patients at diagnosis and various times of their disease (64 samples) and compared the results with FLT3 ITD ratios measured by fragment analysis. We found that NGS could detect variable insertion sites and lengths in a single test for several patients...
September 8, 2015: Oncotarget
Domenico Salemi, Giuseppe Cammarata, Cecilia Agueli, Luigi Augugliaro, Chiara Corrado, Maria Grazia Bica, Stefania Raimondo, Anna Marfia, Valentina Randazzo, Paola Dragotto, Francesco Di Raimondo, Riccardo Alessandro, Francesco Fabbiano, Alessandra Santoro
BACKGROUND: Acute myeloid leukemia (AML) represents a heterogeneous disorder with recurrent chromosomal alterations and molecular abnormalities. Among AML with normal karyotype (NK-AML) FLT3 activating mutation, internal tandem duplication (FLT3-ITD), is present in about 30% of patients, conferring unfavorable outcome. Our previous data demonstrated specific up-regulation of miR-155 in FLT3-ITD+ AML. miR-155 is known to be directly implicated in normal hematopoiesis and in some pathologies such as myeloid hyperplasia and acute lymphoblastic leukemia...
August 2015: Leukemia Research
Ling Li, Ravi Bhatia
PURPOSE OF REVIEW: Recent studies have enhanced our understanding of the role of the SIRT1 deacetylase in regulation of normal hematopoietic stem cells (HSCs) and leukemia stem cells (LSCs), and its importance in regulating autophagy and epigenetic reprogramming in response to metabolic alterations. RECENT FINDINGS: Studies employing conditional deletion mouse models indicate an important role of SIRT1 in maintenance of adult HSCs under conditions of stress. SIRT1 is significantly overexpressed in LSC populations from acute myeloid leukemia (AML) patients with the FLT3-ITD mutation, and maintains their survival, growth and drug resistance, as previously described for chronic myelogenous leukemia (CML)...
July 2015: Current Opinion in Hematology
XiaoYu Yuan, Joshua Koehn, Donna E Hogge
BACKGROUND: A median fluorescence intensity ratio (MFIR) which measures the efflux of mitoxantrone (an ATP Binding Cassette (ABC) transporter substrate) with and without ABC transporter inhibition correlates with expression of MDR1 and BCRP in acute myeloid leukemia (AML) blasts. METHODS: This study evaluates the impacts of the MFIR on AML outcomes and its interaction with detection of the FLT3 ITD. RESULTS: Among 200 newly diagnosed AML patients, an MFIR of ≥ 1...
July 2015: Leukemia Research
Ashkan Emadi, Mariola Sadowska, Brandon Carter-Cooper, Vishal Bhatnagar, Isabella van der Merwe, Mark J Levis, Edward A Sausville, Rena G Lapidus
The incidence of acute myeloid leukemia (AML) is rising and the outcome of current therapy, which has not changed significantly in the last 40 years, is suboptimal. Cellular oxidative state is a credible target to selectively eradicate AML cells, because it is a fundamental property of each cell that is sufficiently different between leukemic and normal cells, yet its aberrancy shared among different AML cells. To this end, we tested whether a short-time treatment of AML cells, including cells with FLT3-ITD mutation, with sub-lethal dose of dichloroacetate (DCA) (priming) followed by pharmacologic dose of arsenic trioxide (ATO) in presence of low-dose DCA could produce insurmountable level of oxidative damage that kill AML cells...
July 2015: Leukemia Research
Li Ye, Meng-Meng Ji, Zi-Min Sun
OBJECTIVE: This study was aimed to detect the FLT3 gene mutation in patients with de-novo acute myeloid leukemia (AML), and to investigate its prognostic value and clinical significance. METHODS: Polymerase chain reaction (PCR) was used to detect FLT3 gene mutation, in bone marrow samples of 54 patients with de novo AML. RESULTS: The incidence of FLT3-ITD mutation in 54 de-novo AML patients was 22.22%, 10 out of 12(83.3%) AML patients were identified with normal karyotype, while 16...
April 2015: Zhongguo Shi Yan Xue Ye Xue za Zhi
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