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https://www.readbyqxmd.com/read/28421420/the-future-of-targeting-flt3-activation-in-aml
#1
REVIEW
Mark B Leick, Mark J Levis
Internal tandem duplications (ITD) and tyrosine-kinase domain (TKD) mutations of the FMS-like tyrosine-kinase 3 (FLT3) can be found in up to one third of patients with acute myeloid leukemia (AML) and confer a poor prognosis. First discovered 20 years ago, these mutations were identified as viable therapeutic targets, and FLT3 tyrosine-kinase inhibitors (TKIs) have been in development for the last decade with steadily increasing potency. However, FLT3-mutated AML often acquires resistance to the growing armamentarium of FLT3 inhibitors through a variety of mechanisms...
April 18, 2017: Current Hematologic Malignancy Reports
https://www.readbyqxmd.com/read/28420723/mitochondrial-bax-determines-the-predisposition-to-apoptosis-in-human-aml
#2
Frank Reichenbach, Cornelius Wiedenmann, Enrico Schalk, Diana Becker, Kathrin Funk, Peter Scholz-Kreisel, Franziska Todt, Denise Wolleschak, Konstanze Dohner, Jens U Marquardt, Florian Heidel, Frank Edlich
Purpose: Cell-to-cell variability in apoptosis signaling contributes to heterogenic responses to cytotoxic stress in clinically heterogeneous neoplasia, such as acute myeloid leukemia (AML). The BCL-2 proteins BAX and BAK can commit mammalian cells to apoptosis and are inhibited by retrotranslocation from the mitochondria into the cytosol. The subcellular localization of BAX and BAK could determine the cellular predisposition to apoptotic death. Experimental design: The relative localization of BAX and BAK was determined by fractionation of AML cell lines and patient samples of a test cohort and a validation cohort...
April 18, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28420416/emerging-therapies-for-acute-myeloid-leukemia
#3
REVIEW
Caner Saygin, Hetty E Carraway
Acute myeloid leukemia (AML) is characterized by clinical and biological heterogeneity. Despite the advances in our understanding of its pathobiology, the chemotherapy-directed management has remained largely unchanged in the past 40 years. However, various novel agents have demonstrated clinical activity, either as single agents (e.g., isocitrate dehydrogenase (IDH) inhibitors, vadastuximab) or in combination with standard induction/consolidation at diagnosis and with salvage regimens at relapse. The classes of agents described in this review include novel cytotoxic chemotherapies (CPX-351 and vosaroxin), epigenetic modifiers (guadecitabine, IDH inhibitors, histone deacetylase (HDAC) inhibitors, bromodomain and extraterminal (BET) inhibitors), FMS-like tyrosine kinase receptor 3 (FLT3) inhibitors, and antibody-drug conjugates (vadastuximab), as well as cell cycle inhibitors (volasertib), B-cell lymphoma 2 (BCL-2) inhibitors, and aminopeptidase inhibitors...
April 18, 2017: Journal of Hematology & Oncology
https://www.readbyqxmd.com/read/28420414/integrated-genomic-analysis-of-mitochondrial-rna-processing-in-human-cancers
#4
Youssef Idaghdour, Alan Hodgkinson
BACKGROUND: The mitochondrial genome is transcribed as continuous polycistrons of RNA containing multiple genes. As a consequence, post-transcriptional events are critical for the regulation of gene expression and therefore all aspects of mitochondrial function. One particularly important process is the m(1)A/m(1)G RNA methylation of the ninth position of different mitochondrial tRNAs, which allows efficient processing of mitochondrial mRNAs and protein translation, and de-regulation of genes involved in these processes has been associated with altered mitochondrial function...
April 18, 2017: Genome Medicine
https://www.readbyqxmd.com/read/28419965/chidamide-in-flt3-itd-positive-acute-myeloid-leukemia-and-the-synergistic-effect-in-combination-with-cytarabine
#5
Xia Li, Xiao Yan, Wenjian Guo, Xin Huang, Jiansong Huang, Mengxia Yu, Zhixin Ma, Yu Xu, ShuJuan Huang, Chenying Li, Yile Zhou, Jie Jin
Chidamide, a novel histone deacetylase inhibitor (HDACi), has been approved for treatment of T-cell lymphomas in multiple clinical trials. It has been demonstrated that chidamide can inhibit cell cycle, promote apoptosis and induce differentiation in leukemia cells, whereas its effect on acute myeloid leukemia (AML) patients with FLT3-ITD mutation has not been clarified. In this study, we found that chidamide specifically induced G0/G1 arrest and apoptosis in FLT3-ITD positive AML cells in a concentration and time-dependent manner...
April 15, 2017: Biomedicine & Pharmacotherapy, Biomédecine & Pharmacothérapie
https://www.readbyqxmd.com/read/28418873/combined-inhibition-of-gli-and-flt3-signaling-leads-to-effective-anti-leukemic-effects-in-human-acute-myeloid-leukemia
#6
Emily-Marie Latuske, Hauke Stamm, Marianne Klokow, Gabi Vohwinkel, Jana Muschhammer, Carsten Bokemeyer, Manfred Jücker, Maxim Kebenko, Walter Fiedler, Jasmin Wellbrock
Activation of the Hedgehog pathway has been implicated in the pathogenesis of several tumor types including myeloid leukemia. Previously we demonstrated that overexpression of Hedgehog downstream mediators GLI1/2 confers an adverse prognosis to patients with acute myeloid leukemia (AML) and is correlated with a FLT3 mutated status. To analyze a possible non-canonical activation of the Hedgehog pathway via FLT3 and PI3K, we performed blocking experiments utilizing inhibitors for FLT3 (sunitinib), PI3K (PF-04691502) and GLI1/2 (GANT61) in FLT3-mutated and FLT3 wildtype AML cell lines and primary blasts...
March 16, 2017: Oncotarget
https://www.readbyqxmd.com/read/28408464/targetable-kinase-gene-fusions-in-high-risk-b-all-a-study-from-the-children-s-oncology-group
#7
Shalini C Reshmi, Richard C Harvey, Kathryn G Roberts, Eileen Stonerock, Amy Smith, Heather Jenkins, I-Ming Chen, Marc Valentine, Yu Liu, Yongjin Li, Ying Shao, John Easton, Debbie Payne-Turner, Zhaohui Gu, Thai Hoa Tran, Jonathan V Nguyen, Meenakshi Devidas, Yunfeng Dai, Nyla A Heerema, Andrew J Carroll, Elizabeth A Raetz, Michael J Borowitz, Brent L Wood, Anne L Angiolillo, Michael J Burke, Wanda L Salzer, Patrick A Zweidler-McKay, Karen R Rabin, William L Carroll, Jinghui Zhang, Mignon L Loh, Charles G Mullighan, Cheryl L Willman, Julie M Gastier-Foster, Stephen P Hunger
Philadelphia chromosome-like acute lymphoblastic leukemia (Ph-like ALL) is a high-risk subtype characterized by genomic alterations that activate cytokine receptor and kinase signaling. We examined the frequency and spectrum of targetable genetic lesions in a retrospective cohort of 1389 consecutively diagnosed childhood B-ALL patients with high-risk clinical features and/or elevated minimal residual disease at the end of remission induction therapy. The Ph-like gene expression profile was identified in 341 of 1389 patients, 57 of which were excluded from additional analysis because of the presence of BCR-ABL1 (n=46) or ETV6-RUNX1 (n=11)...
April 13, 2017: Blood
https://www.readbyqxmd.com/read/28407515/high-cd200-expression-is-associated-with-poor-prognosis-in-cytogenetically-normal-acute-myeloid-leukemia-even-in-flt3-itd-npm1-patients
#8
Mario Tiribelli, Donatella Raspadori, Antonella Geromin, Margherita Cavallin, Santina Sirianni, Erica Simeone, Monica Bocchia, Renato Fanin, Daniela Damiani
Overexpression of CD200, a trans-membrane protein belonging to the immunoglobulin superfamily, has been associated with poor prognosis in patients with acute myeloid leukemia (AML). As few data are available in the subset of cytogenetically-normal (CN) AML, we retrospectively evaluated the correlations between CD200 expression and response to therapy in a series of 139 adults with CN-AML. CD200 was expressed in 67/139 (48%) cases; 18 of them (28%) expressed CD200 at high intensity. No differences in CD200 expression rate were observed according to age, WBC count, type of leukemia, FLT3 or NMP1 mutation, and CD56 expression...
April 4, 2017: Leukemia Research
https://www.readbyqxmd.com/read/28395440/-prognostic-significance-of-blood-count-at-the-time-of-achieving-morphologic-leukemia-free-state-in-adults-with-acute-myeloid-leukemia
#9
X Ren, T Zhao, J Wang, H H Zhu, H Jiang, J S Jia, S M Yang, B Jiang, D B Wang, X J Huang, Q Jiang
Objective: To explore prognostic significance of blood count at the time of achieving first morphologic leukemia-free state[complete remission (CR, ANC ≥1×10(9)/L and PLT ≥100×10(9)/L) , CR with incomplete PLT recovery (CRp) and CR with incomplete ANC and PLT recovery (CRi) ]in adult patients with de novo acute myeloid leukemia (AML) . Methods: From January 2008 to February 2016, data of consecutive newly-diagnosed AML (non-APL) adults who received continuous chemotherapy in our hospital were analyzed retrospectively...
March 14, 2017: Zhonghua Xue Ye Xue za Zhi, Zhonghua Xueyexue Zazhi
https://www.readbyqxmd.com/read/28391291/rejuvenation-of-mucosal-immunosenescence-by-adipose-tissue-derived-mesenchymal-stem-cells
#10
Akitoshi Tsuruhara, Kazuyoshi Aso, Daisuke Tokuhara, Junichiro Ohori, Masaki Kawabata, Yuichi Kurono, Jerry R McGhee, Kohtaro Fujihashi
Age-associated alterations in the mucosal immune system are generally termed mucosal immunosenescence. The major change seen in the aged mucosa is a failure to elicit an antigen-specific secretory IgA (SIgA) antibody response, which is a central player for host defense from various pathogens at mucosal surfaces. In this regard, it would be a first priority to compensate for mucosal dysregulation in the elderly in order to maintain their health in aging. We have successfully established antigen-specific SIgA antibody responses in aged (2 years old) mice, which provide protective immunity from Streptococcus pneumoniae and influenza virus infections, by using a new adjuvant system consisting of a plasmid encoding Flt3 ligand (pFL) and CpG ODN...
January 1, 2017: International Immunology
https://www.readbyqxmd.com/read/28390194/stat5-deficiency-decreases-transcriptional-heterogeneity-and-supports-emergence-of-hematopoietic-sub-populations
#11
Zhengqi Wang, Kevin D Bunting
Aging is associated with significant changes in hematopoiesis, including clonal dominance, anemia, myeloid malignancies, and reduced activation of signal transducer and activator of transcription 5 (Stat5). In previous studies, Stat5 deletion surprisingly amplified FLT3/ITD+ myeloid expansion or Myc-driven lymphoid expansion. Here we show that Stat5 deficiency has a strong impact upon transcriptional heterogeneity in single sorted c-Kit+Lin-Sca-1+ (KLS) cells or CD150+CD48- KLS long-term repopulating hematopoietic stem cells (LT-HSC)...
April 4, 2017: Oncotarget
https://www.readbyqxmd.com/read/28387928/efficacy-and-feasibility-of-sorafenib-as-a-maintenance-agent-after-allogeneic-hematopoietic-stem-cell-transplantation-for-fms-like-tyrosine-kinase-3-mutated-acute-myeloid-leukemia
#12
Giorgia Battipaglia, Annalisa Ruggeri, Radwan Massoud, Jean El Cheikh, Matthieu Jestin, Ahmad Antar, Syed Osman Ahmed, Walid Rasheed, Marwan Shaheen, Ramdane Belhocine, Eolia Brissot, Remy Dulery, Sandra Eder, Federica Giannotti, Francoise Isnard, Simona Lapusan, Marie-Therese Rubio, Anne Vekhoff, Mahmoud Aljurf, Ollivier Legrand, Mohamad Mohty, Ali Bazarbachi
BACKGROUND: Sorafenib has shown encouraging results in patients with Fms-like tyrosine kinase 3 (FLT3)-positive acute myeloid leukemia. Its role after allogeneic stem cell transplantation (HSCT) has been reported in a few cases with encouraging results. METHODS: The authors describe the use of sorafenib as a maintenance agent after HSCT in 27 patients with FLT3-positive acute myeloid leukemia. RESULTS: The median age of the patients was 46 years (range, 15-57 years)...
April 7, 2017: Cancer
https://www.readbyqxmd.com/read/28381396/caspase-3-controls-aml1-eto-driven-leukemogenesis-via-autophagy-modulation-in-a-ulk1-dependent-manner
#13
Na Man, Yurong Tan, Xiao-Jian Sun, Fan Liu, Guoyan Cheng, Sarah Greenblatt, Camilo Martinez, Daniel L Karl, Koji Ando, Ming Sun, Dan Hou, Bingyi Chen, Mingjiang Xu, Feng-Chun Yang, Zhu Chen, Saijuan Chen, Stephen D Nimer, Lan Wang
AML1-ETO (AE), a fusion oncoprotein, generated by the t(8;21), can trigger acute myeloid leukemia (AML) in collaboration with mutations including c-Kit, ASXL1/2, FLT3, N-RAS, and K-RAS. Caspase-3, a key executor among its family, plays multiple roles in cellular processes, including hematopoietic development and leukemia progression. Caspase-3 was revealed to directly cleave AE in vitro, suggesting that AE may accumulate in a Caspase-3 compromised background and thereby accelerate leukemogenesis. Therefore, we developed a Caspase-3 knockout genetic mouse model of AML and found that loss of Caspase-3 actually delayed AML1-ETO9a (AE9a)-driven leukemogenesis, indicating that Caspase-3 may play distinct roles in the initiation and/or progression of AML...
April 5, 2017: Blood
https://www.readbyqxmd.com/read/28373471/continuation-of-a-levonorgestrel-intrauterine-device-during-hematopoietic-stem-cell-transplant-a-case-report
#14
Paula C Brady, Robert J Soiffer, Elizabeth S Ginsburg
BACKGROUND: During treatment of hematologic malignancies in premenopausal women, both menstrual suppression and contraception are crucial. Continuation of hormonal intrauterine devices (IUDs) - widely used and highly effective contraceptives that also decrease menstrual flow - is controversial during hematopoietic stem cell transplants (SCTs) due to infectious and vaginal bleeding concerns. CASE REPORT: A 23-year-old nulligravid female was diagnosed with acute myeloid leukemia (AML, positive for FLT3-ITD, DNMT3A and RUNX1, with normal cytogenetics)...
April 2017: Anticancer Research
https://www.readbyqxmd.com/read/28370339/long-term-impact-of-hyperleukocytosis-in-newly-diagnosed-acute-myeloid-leukemia-patients-undergoing-allogeneic-stem-cell-transplantation-an-analysis-from-the-acute-leukemia-working-party-of-the-ebmt
#15
Jonathan Canaani, Myriam Labopin, Gerard Socié, Anne Nihtinen, Anne Huynh, Jan Cornelissen, Eric Deconinck, Tobias Gedde-Dahl, Edouard Forcade, Patrice Chevallier, Jean Henri Bourhis, Didier Blaise, Mohamad Mohty, Arnon Nagler
Up to 20% of acute myeloid leukemia (AML) patients present initially with hyperleukocytosis, placing them at increased risk for early mortality during induction. Yet, it is unknown whether hyperleukocytosis still retains prognostic value for AML patients undergoing hematopoietic stem cell transplantation (HSCT). Furthermore, it is unknown whether hyperleukocytosis holds prognostic significance when modern molecular markers such as FLT3-ITD and NPM1 are accounted for. To determine whether hyperleukocytosis is an independent prognostic factor influencing outcome in transplanted AML patients we performed a retrospective analysis using the registry of the acute leukemia working party of the EBMT...
March 28, 2017: American Journal of Hematology
https://www.readbyqxmd.com/read/28368672/idarubicin-dose-escalation-during-consolidation-therapy-for-adult-acute-myeloid-leukemia
#16
Kenneth F Bradstock, Emma Link, Juliana Di Iulio, Jeff Szer, Paula Marlton, Andrew H Wei, Arno Enno, Anthony Schwarer, Ian D Lewis, James D'Rozario, Luke Coyle, Gavin Cull, Phillip Campbell, Michael F Leahy, Uwe Hahn, Paul Cannell, Campbell Tiley, Ray M Lowenthal, John Moore, Kimberly Cartwright, Ilona Cunningham, John Taper, Andrew Grigg, Andrew W Roberts, Warwick Benson, Mark Hertzberg, Sandra Deveridge, Philip Rowlings, Anthony K Mills, Devinder Gill, Peter Bardy, Lynda Campbell, John F Seymour
Purpose Higher doses of the anthracycline daunorubicin during induction therapy for acute myeloid leukemia (AML) have been shown to improve remission rates and survival. We hypothesized that improvements in outcomes in adult AML may be further achieved by increased anthracycline dose during consolidation therapy. Patients and Methods Patients with AML in complete remission after induction therapy were randomly assigned to receive two cycles of consolidation therapy with cytarabine 100 mg/m(2) daily for 5 days, etoposide 75 mg/m(2) daily for 5 days, and idarubicin 9 mg/m(2) daily for either 2 or 3 days (standard and intensive arms, respectively)...
April 3, 2017: Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology
https://www.readbyqxmd.com/read/28358966/flt3-mutation-testing-in-acute-myeloid-leukemia
#17
Arjun Gupta, David S Viswanatha, Mrinal M Patnaik
No abstract text is available yet for this article.
March 30, 2017: JAMA Oncology
https://www.readbyqxmd.com/read/28353016/new-therapeutic-strategies-in-acute-lymphocytic-leukemia
#18
REVIEW
Louise M Man, Amy L Morris, Michael Keng
Most drugs used in standard regimens for acute lymphoblastic leukemia (ALL) were developed more than 30 years ago. Since that time, several new drugs have been developed and incorporated into ALL treatment. In spite of this, novel therapeutic approaches are still needed to improve outcomes for high-risk or relapsed ALL. This manuscript discusses newer treatment strategies, including purine nucleoside analogs, monoclonal antibodies, antibody drug conjugates, mammalian target of rapamycin (mTOR) inhibitors, proteasome inhibitors, histone deacetylase (HDAC) inhibitors, hypomethylating agents, spleen tyrosine kinase inhibitors, Bruton's tyrosine kinase (BTK) inhibitors, Janus kinase-signal transducer and activator of transcription (JAK-STAT) inhibitors, anti-programmed cell death protein (anti-PD-1) antibodies, mitogen-activated protein kinase (MEK) inhibitors, CXCR4 antagonists, poly (ADP-ribose) polymerase (PARP) inhibitors, and FMS-like tyrosine kinase 3 (FLT3) inhibitors...
March 28, 2017: Current Hematologic Malignancy Reports
https://www.readbyqxmd.com/read/28336808/potent-dual-bet-bromodomain-kinase-inhibitors-as-value-added-multi-targeted-chemical-probes-and-cancer-therapeutics
#19
Stuart W Ember, Que T Lambert, Norbert Berndt, Steven Gunawan, Muhammad Ayaz, Marilena Tauro, Jin-Yi Zhu, Paula J Cranfill, Patricia Greninger, Conor C Lynch, Cyril H Benes, Harshani R Lawrence, Gary W Reuther, Nicholas J Lawrence, Ernst Schonbrunn
Synergistic action of kinase and BET bromodomain inhibitors in cell killing has been reported for a variety of cancers. Using the chemical scaffold of the JAK2 inhibitor TG101348 we developed and characterized single agents which potently and simultaneously inhibit BRD4 and a specific set of oncogenic tyrosine kinases including JAK2, FLT3, RET, and ROS1. Lead compounds showed on-target inhibition in several blood cancer cell lines and were highly efficacious at inhibiting the growth of hematopoietic progenitor cells from myeloproliferative neoplasm (MPN) patients...
March 23, 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/28336242/pacritinib-versus-best-available-therapy-for-the-treatment-of-myelofibrosis-irrespective-of-baseline-cytopenias-persist-1-an-international-randomised-phase-3-trial
#20
Ruben A Mesa, Alessandro M Vannucchi, Adam Mead, Miklos Egyed, Anita Szoke, Aleksandr Suvorov, Janos Jakucs, Andrew Perkins, Ritam Prasad, Jiri Mayer, Judit Demeter, Peter Ganly, Jack W Singer, Huafeng Zhou, James P Dean, Peter A Te Boekhorst, Jyoti Nangalia, Jean-Jacques Kiladjian, Claire N Harrison
BACKGROUND: Available therapies for myelofibrosis can exacerbate cytopenias and are not indicated for patients with severe thrombocytopenia. Pacritinib, which inhibits both JAK2 and FLT3, induced spleen responses with limited myelosuppression in phase 1/2 trials. We aimed to assess the efficacy and safety of pacritinib versus best available therapy in patients with myelofibrosis irrespective of baseline cytopenias. METHODS: This international, multicentre, randomised, phase 3 trial (PERSIST-1) was done at 67 sites in 12 countries...
March 20, 2017: Lancet Haematology
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