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https://www.readbyqxmd.com/read/28223820/flt3-inhibitors-clinical-potential-in-acute-myeloid-leukemia
#1
REVIEW
Marie-Anne Hospital, Alexa S Green, Thiago T Maciel, Ivan C Moura, Anskar Y Leung, Didier Bouscary, Jerome Tamburini
Acute myeloid leukemia (AML) is an aggressive hematopoietic malignancy that is cured in as few as 15%-40% of cases. Tremendous improvements in AML prognostication arose from a comprehensive analysis of leukemia cell genomes. Among normal karyotype AML cases, mutations in the FLT3 gene are the ones most commonly detected as having a deleterious prognostic impact. FLT3 is a transmembrane tyrosine kinase receptor, and alterations of the FLT3 gene such as internal tandem duplications (FLT3-ITD) deregulate FLT3 downstream signaling pathways in favor of increased cell proliferation and survival...
2017: OncoTargets and Therapy
https://www.readbyqxmd.com/read/28222251/prognostic-methylation-markers-for-overall-survival-in-cytogenetically-normal-patients-with-acute-myeloid-leukemia-treated-on-swog-trials
#2
Xiaoyu Qu, Megan Othus, Jerry Davison, Yu Wu, Liying Yan, Soheil Meshinchi, Fabiana Ostronoff, Elihu H Estey, Jerry P Radich, Harry P Erba, Frederick R Appelbaum, Min Fang
BACKGROUND: Aberrant DNA methylation is known to occur in patients with acute myeloid leukemia (AML), whereas methylation signatures and prognostic markers have been proposed. The objective of the current study was to evaluate all CpG sites of the genome and identify prognostic methylation markers for overall survival in patients with AML with normal karyotype (AML-NK). METHODS: AML-NK samples from 7 SWOG trials were analyzed using a novel genome-wide approach called "CHARMcox" (comprehensive high-throughput array-based relative methylation analysis combined with the Cox proportional hazards model) controlling for known clinical covariates...
February 21, 2017: Cancer
https://www.readbyqxmd.com/read/28220349/clofarabine-based-chemotherapy-as-a-bridge-to-transplant-in-the-setting-of-refractory-or-relapsed-acute-myeloid-leukemia-after-at-least-one-previous-unsuccessful-salvage-treatment-containing-fludarabine-a-single-institution-experience
#3
Alfredo Molteni, Marta Riva, Emanuele Ravano, Laura Marbello, Valentina Mancini, Giovanni Grillo, Elisa Zucchetti, Rosa Greco, Roberto Cairoli
For refractory or relapsed acute myeloid leukemia patients, allogeneic hematopoietic stem cell transplantation is the only curative treatment option, but the disease must be in remission before this can be attempted. "Salvage" therapy regimens containing high-dose cytarabine plus fludarabine or cladribine with or without anthracyclines or plus mitoxantrone and etoposide fail in 30-50% of cases. We report the outcome of 14 patients treated with a clofarabine-based treatment administered after at least one failed fludarabine-based "salvage" attempt in a "real life" (outside a clinical trial) context...
February 20, 2017: International Journal of Hematology
https://www.readbyqxmd.com/read/28219218/-prognostic-significance-of-early-assessment-of-minimal-residual-disease-in-acute-myeloid-leukemia-with-mutated-npm1-patients
#4
T Zhao, H H Zhu, J Wang, J S Jia, S M Yang, H Jiang, J Lu, H Chen, L P Xu, X H Zhang, B Jiang, G R Ruan, D B Wang, X J Huang, Q Jiang
Objective: To explore prognostic significance of early assessment of minimal residual leukemia (MRD) in adult patients with de novo acute myeloid leukemia (AML) with mutated NPM1. Methods: The response, NPM1 mutated transcript level after induction chemotherapy and the first 2 cycles of consolidation chemotherapy, disease-free survival (DFS) and overall survival (OS) in 137 patients with AML with NPM1 mutations of A, B and D were retrospectively analyzed. Results: Data of 137 patients were collected, 67 were male, the median age was 49 years (16-67 years) , 107 (78...
January 14, 2017: Zhonghua Xue Ye Xue za Zhi, Zhonghua Xueyexue Zazhi
https://www.readbyqxmd.com/read/28214896/the-genomic-landscape-of-pax5-ikzf1-and-cdkn2a-b-alterations-in-b-cell-precursor-acute-lymphoblastic-leukemia
#5
Zhishuo Ou, Maureen Sherer, Jane Casey, Heather A Bakos, Kathleen Vitullo, Jie Hu, Erika Friehling, Susanne M Gollin, Urvashi Surti, Svetlana A Yatsenko
We present a comprehensive comparison of PAX5,IKZF1, and CDKN2A/B abnormalities in 21 B-cell precursor acute lymphoblastic leukemia (B-ALL) patients studied by aCGH and gene-specific FISH assays. In our cohort of B-ALL patients, alterations of IKZF1, PAX5, and CDKN2A/B were detected by aCGH analysis in 43, 52, and 57% of samples, respectively. Deletions of IKZF1 were present in 9 samples, including 5 cases positive for both PAX5 and IKZF1 deletions, implying digenic impairment. Furthermore, all cases with IKZF1 deletions also had additional genomic alterations, including BCR-ABL1 gene fusions, PAX5 deletions, CDKN2A/B deletions, and FLT3 amplification...
February 18, 2017: Cytogenetic and Genome Research
https://www.readbyqxmd.com/read/28213513/runx1-cooperates-with-flt3-itd-to-induce-leukemia
#6
Kira Behrens, Katrin Maul, Nilgün Tekin, Neele Kriebitzsch, Daniela Indenbirken, Vladimir Prassolov, Ursula Müller, Hubert Serve, Jörg Cammenga, Carol Stocking
Acute myeloid leukemia (AML) is induced by the cooperative action of deregulated genes that perturb self-renewal, proliferation, and differentiation. Internal tandem duplications (ITDs) in the FLT3 receptor tyrosine kinase are common mutations in AML, confer poor prognosis, and stimulate myeloproliferation. AML patient samples with FLT3-ITD express high levels of RUNX1, a transcription factor with known tumor-suppressor function. In this study, to understand this paradox, we investigated the impact of RUNX1 and FLT3-ITD coexpression...
February 17, 2017: Journal of Experimental Medicine
https://www.readbyqxmd.com/read/28197208/molecular-mutations-and-their-cooccurrences-in-cytogenetically-normal-acute-myeloid-leukemia
#7
REVIEW
Mengning Wang, Chuanwei Yang, Le Zhang, Dale G Schaar
Adult acute myeloid leukemia (AML) clinically is a disparate disease that requires intensive treatments ranging from chemotherapy alone to allogeneic hematopoietic cell transplantation (allo-HCT). Historically, cytogenetic analysis has been a useful prognostic tool to classify patients into favorable, intermediate, and unfavorable prognostic risk groups. However, the intermediate-risk group, consisting predominantly of cytogenetically normal AML (CN-AML), itself exhibits diverse clinical outcomes and requires further characterization to allow for more optimal treatment decision-making...
2017: Stem Cells International
https://www.readbyqxmd.com/read/28194038/itd-mutation-in-flt3-tyrosine-kinase-promotes-warburg-effect-and-renders-therapeutic-sensitivity-to-glycolytic-inhibition
#8
H-Q Ju, G Zhan, A Huang, Y Sun, S Wen, J Yang, W-H Lu, R-H Xu, J Li, Y Li, G Garcia-Manero, P Huang, Y Hu
Internal tandem duplication (ITD) mutation in Fms-like tyrosine kinase 3 gene (FLT3/ITD) represents an unfavorable genetic change in acute myeloid leukemia (AML) and is associated with poor prognosis. Metabolic alterations have been involved in tumor progression and attracted interest as a target for therapeutic intervention. However, few studies analyzed the adaptations of cellular metabolism in the context of FLT3/ITD mutation. Here, we report that FLT3/ITD causes a significant increase in aerobic glycolysis through AKT-mediated upregulation of mitochondrial hexokinase (HK2), and renders the leukemia cells highly dependent on glycolysis and sensitive to pharmacological inhibition of glycolytic activity...
February 14, 2017: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
https://www.readbyqxmd.com/read/28193779/combination-targeted-therapy-to-disrupt-aberrant-oncogenic-signaling-and-reverse-epigenetic-dysfunction-in-idh2-and-tet2-mutant-acute-myeloid-leukemia
#9
Alan H Shih, Cem Meydan, Kaitlyn Shank, Francine E Garrett-Bakelman, Patrick S Ward, Andrew Intlekofer, Abbas Nazir, Eytan Stein, Kristina Knapp, Jacob Glass, Jeremy Travins, Kim Straley, Camelia Gliser, Chris Mason, Katharine Yen, Craig B Thompson, Ari Melnick, Ross L Levine
Genomic studies in acute myeloid leukemias (AML) have identified mutations which drive altered DNA methylation, including TET2 and IDH2. Here we show that models of AMLs resulting from TET2 or IDH2 mutations combined with FLT3ITD mutations are sensitive to 5-Azacytidine or to the IDH2 inhibitor AG-221, respectively. 5-Azacytidine and AG-221 treatment induced an attenuation of aberrant DNA methylation and transcriptional output, and resulted in a reduction in leukemic blasts consistent with anti-leukemic activity...
February 13, 2017: Cancer Discovery
https://www.readbyqxmd.com/read/28185526/low-expression-of-ash2l-protein-correlates-with-a-favorable-outcome-in-acute-myeloid-leukemia
#10
Jill S Butler, Yi Hua Qiu, Nianxiang Zhang, Suk-Young Yoo, Kevin R Coombes, Sharon Y R Dent, Steven M Kornblau
ASH2L encodes a trithorax group protein that is a core component of all characterized mammalian histone H3K4 methyltransferase complexes, including mixed lineage leukemia (MLL) complexes. ASH2L protein levels in primary leukemia patient samples have not yet been defined. We analyzed ASH2L protein expression in 511 primary AML patient samples using reverse phase protein array (RPPA) technology. We discovered that ASH2L expression is significantly increased in a subset of patients carrying fms-related tyrosine kinase 3 (FLT3) mutations...
May 2017: Leukemia & Lymphoma
https://www.readbyqxmd.com/read/28175536/337%C3%A2-expansion-of-dendritic-cells-using-flt3-ligand-to-treat-glioblastoma-a-preclinical-study
#11
Tomas Garzon-Muvdi, Antonella Mangraviti, Debebe Theodros, Eileen Kim, Michael Jay Yellin, Henry Marsh, Michael Lim
No abstract text is available yet for this article.
August 1, 2016: Neurosurgery
https://www.readbyqxmd.com/read/28167452/tet2-exon-2-skipping-is-an-independent-favorable-prognostic-factor-for-cytogenetically-normal-acute-myelogenous-leukemia-aml-tet2-exon-2-skipping-in-aml
#12
Aminetou Mint Mohamed, Marie Balsat, Catherine Koering, Delphine Maucort-Boulch, Nicolas Boissel, Lea Payen-Gay, Meyling Cheok, Hussein Mortada, Didier Auboeuf, Christiane Pinatel, Mohamed El-Hamri, Isabelle Tigaud, Sandrine Hayette, Charles Dumontet, Emeline Cros, Pascale Flandrin-Gresta, Olivier Nibourel, Claude Preudhomme, Xavier Thomas, Franck-Emmanuel Nicolini, Françoise Solly, Denis Guyotat, Lydia Campos, Mauricette Michallet, Antony Ceraulo, Franck Mortreux, Eric Wattel
In AML, approximately one-third of expressed genes are abnormally spliced, including aberrant TET2 exon 2 expression. In a discovery cohort (n=99), TET2 exon 2 skipping (TET2E2S) was found positively associated with a significant reduction in the cumulative incidence of relapse (CIR). Age, cytogenetics, and TET2E2S were independent prognostic factors for disease-free survival (DFS), and favorable effects on outcomes predominated in cytogenetic normal (CN)-AML and younger patients. Using the same cutoff in a validation cohort of 86 CN-AML patients, TET2E2S(high) patients were found to be younger than TET2(low) patients without a difference in the rate of complete remission...
January 16, 2017: Leukemia Research
https://www.readbyqxmd.com/read/28164543/detection-the-frequency-and-characteristics-of-flt3-internal-tandem-duplication-mutations-by-capillary-electrophoresis-assay-and-next-generation-sequencing-in
#13
Liang Ma, Yongyue Cao, Yongwei Jiang, Xiao Cong, Shuang Lu, Jun Shen, Qian Liu, Chengwu Han, Yuliang Zhan, Yongtong Cao
BACKGROUND: FLT3-internal tandem duplication mutations (ITDs) are found in approximately 30% of patients with acute myeloid leukemia (AML) and are markers of poor prognosis. However, the characteristics of FLT3/ ITDs in Chinese AML patients have rarely been reported. The aim of this study was to analyze the frequency and characteristics of FLT3/ITDs in Chinese AML patients. METHODS: In the selected 152 cases of Chinese AML patients, capillary electrophoresis (CE) was used to analyze the frequency and characteristics of FLT3/ITDs...
October 1, 2016: Clinical Laboratory
https://www.readbyqxmd.com/read/28164537/flt3-gene-mutation-profile-and-prognosis-in-adult-acute-myeloid-leukemia
#14
Aileen Azari-Yam, Javad Tavakkoly-Bazzaz, Yousef Semnani, Elham Davoudi-Dehaghani, Robabeh Ghodssi-Ghassemabadi, Soodeh Kianfar, Ameneh Saadat, Mahboobeh Masoudifard, Marjan Yaghmaie, Kamran Alimoghaddam, Ardeshir Ghavamzadeh, Sirous Zeinali
BACKGROUND: Internal tandem duplication (ITD) of FMS-related tyrosine kinase 3 (FLT3) gene, which occurs in exons 14 and 15, is one of the most prevalent somatic mutations in adult acute myeloid leukemia (AML) and has biological, prognostic, and therapeutic implications. The prognostic importance of codon 835 tyrosine kinase domain (TKD) mutation (exon 20), which occurs relatively frequently in adult AML, is often debated. We aimed to study the FLT3 gene mutation profile and prognosis in 139 adult Iranian patients with newly diagnosed AML...
October 1, 2016: Clinical Laboratory
https://www.readbyqxmd.com/read/28163010/use-of-wilms-tumor-1-gene-expression-as-a-reliable-marker-for-prognosis-and-minimal-residual-disease-monitoring-in-acute-myeloid-leukemia-with-normal-karyotype-patients
#15
Irena Marjanovic, Teodora Karan-Djurasevic, Milena Ugrin, Marijana Virijevic, Ana Vidovic, Dragica Tomin, Nada Suvajdzic Vukovic, Sonja Pavlovic, Natasa Tosic
BACKGROUND: Acute myeloid leukemia with normal karyotype (AML-NK) represents the largest group of AML patients classified with an intermediate prognosis. A constant need exists to introduce new molecular markers for more precise risk stratification and for minimal residual disease (MRD) monitoring. PATIENTS AND METHODS: Quantitative assessment of Wilms tumor 1 (WT1) gene transcripts was performed using real-time polymerase chain reaction. The bone marrow samples were collected at the diagnosis from 104 AML-NK patients and from 34 of these patients during follow-up or disease relapse...
January 11, 2017: Clinical Lymphoma, Myeloma & Leukemia
https://www.readbyqxmd.com/read/28159598/predictive-value-of-pretransplantation-molecular-minimal-residual-disease-assessment-by-wt1-gene-expression-in-flt3-positive-acute-myeloid-leukemia
#16
Anna Candoni, Federico De Marchi, Francesca Zanini, Maria Elena Zannier, Erica Simeone, Eleonora Toffoletti, Alexsia Chiarvesio, Michela Cerno, Carla Filì, Francesca Patriarca, Renato Fanin
The FMS-like tyrosine kinase 3 (FLT3) mutation in acute myeloid leukemia (AML) is a negative prognostic factor and, in these cases, allogeneic stem cell transplantation (allo-SCT) can represent an important therapeutic option, especially if performed in complete remission (CR). However, it is increasingly clear that not all cytological CRs (cCRs) are the same and that minimal residual disease (MRD) before allo-SCT could have an impact on AML outcome. Unfortunately, FLT3, due its instability of expression, is still not considered a good molecular MRD marker...
February 1, 2017: Experimental Hematology
https://www.readbyqxmd.com/read/28154969/what-is-the-best-daunorubicin-dose-and-schedule-for-acute-myeloid-leukemia-induction
#17
REVIEW
Priyanka Pophali, Mark Litzow
Daunorubicin dose intensification for induction in acute myeloid leukemia has been reported as an effective strategy in recent trials to improve patient outcomes without worsening treatment-related toxicity. Based on available evidence, 90 mg/m(2) of daunorubicin given for three consecutive days (cumulative dose 270 mg/m(2)) as a part of the "7 + 3" induction regimen along with cytarabine is the most effective dose to achieve a complete remission as well as improve survival in patients who can tolerate it...
January 2017: Current Treatment Options in Oncology
https://www.readbyqxmd.com/read/28152414/coexisting-and-cooperating-mutations-in-npm1-mutated-acute-myeloid-leukemia
#18
Jay L Patel, Jonathan A Schumacher, Kimberly Frizzell, Shelly Sorrells, Wei Shen, Adam Clayton, Rakhi Jattani, Todd W Kelley
NPM1 insertion mutations represent a common recurrent genetic abnormality in acute myeloid leukemia (AML) patients. The frequency of these mutations varies from approximately 30% overall up to 50% in patients with a normal karyotype. Several recent studies have exploited advances in massively parallel sequencing technology to shed light on the complex genomic landscape of AML. We hypothesize that variant allele fraction (VAF) data derived from massively parallel sequencing studies may provide further insights into the clonal architecture and pathogenesis of NPM1-driven leukemogenesis...
January 23, 2017: Leukemia Research
https://www.readbyqxmd.com/read/28142203/flt3-as-a-marker-of-minimal-residual-disease-time-to-re-think
#19
Mark Levis
No abstract text is available yet for this article.
January 31, 2017: American Journal of Hematology
https://www.readbyqxmd.com/read/28138160/impact-of-salvage-regimens-on-response-and-overall-survival-in-acute-myeloid-leukemia-with-induction-failure
#20
M Wattad, D Weber, K Döhner, J Krauter, V I Gaidzik, P Paschka, M Heuser, F Thol, T Kindler, M Lübbert, H R Salih, A Kündgen, H-A Horst, P Brossart, K Götze, D Nachbaur, C-H Köhne, M Ringhoffer, G Wulf, G Held, H Salwender, A Benner, A Ganser, H Döhner, R F Schlenk
We evaluated the impact of salvage regimens and allogeneic hematopoietic cell transplantation (allo-HCT) in acute myeloid leukemia (AML) with induction failure. Between 1993 and 2009, 3324 patients with newly diagnosed AML were enrolled in 5 prospective treatment trials of the German-Austrian AML Study Group. After first induction therapy with idarubicin, cytarabine and etoposide (ICE), 845 patients had refractory disease. In addition, 180 patients, although responding to first induction, relapsed after second induction therapy...
February 10, 2017: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
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