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Flt3 itd

Alex Pezzotta, Mara Mazzola, Marco Spreafico, Anna Marozzi, Anna Pistocchi
The genes of the cohesin complex exert different functions, ranging from the adhesion of sister chromatids during the cell cycle, DNA repair, gene expression and chromatin architecture remodeling. In recent years, the improvement of DNA sequencing technologies allows the identification of cohesin mutations in different tumors such as acute myeloid leukemia (AML), acute megakaryoblastic leukemia (AMKL), and myelodysplastic syndromes (MDS). However, the role of cohesin dysfunction in cancer insurgence remains elusive...
2019: Frontiers in Cell and Developmental Biology
Dong Chen, Siyuan Xia, Mei Wang, Ruiting Lin, Yuancheng Li, Hui Mao, Mike Aguiar, Christopher A Famulare, Alan H Shih, Cameron W Brennan, Xue Gao, Yaozhu Pan, Shuangping Liu, Jun Fan, Lingtao Jin, Lina Song, An Zhou, Joydeep Mukherjee, Russell O Pieper, Ashutosh Mishra, Junmin Peng, Martha Arellano, William G Blum, Sagar Lonial, Titus J Boggon, Ross L Levine, Jing Chen
Isocitrate dehydrogenase 1 (IDH1) is important for reductive carboxylation in cancer cells, and IDH1 R132H mutant plays a pathogenic role in cancers including acute myeloid leukemia (AML). However, the regulatory mechanisms modulating IDH1 mutant and/or wild-type (WT) function remain unknown. Here we show that two groups of tyrosine kinases (TKs) enhance the activation of IDH1 mutant and WT through preferential Y42 or Y391 phosphorylation. Mechanistically, Y42 phosphorylation occurs in IDH1 monomers, which promotes dimer formation with enhanced substrate (isocitrate or a-ketoglutarate) binding, while Y42-phosphorylated dimers show attenuated disruption to monomers...
March 12, 2019: Cancer Discovery
Ya-Chen Ko, Chung-Yi Hu, Zheng-Hau Liu, Hwei-Fang Tien, Da-Liang Ou, Hsiung-Fei Chien, Liang-In Lin
Internal tandem duplication of FLT3 juxtamembrane domain (FLT3-ITD)-positive acute myeloid leukemia (AML) leads to poor clinical outcomes after chemotherapy. We aimed to establish a cytarabine-resistant line from FLT3 -ITD-positive MV4-11 (MV4-11-P) cells and examine the development of resistance. The FLT3 -ITD mutation was retained in MV4-11-R; however, the protein was underglycosylated and less phosphorylated in these cells. Moreover, the phosphorylation of ERK1/2, Akt, MEK1/2 and p53 increased in MV4-11-R...
March 11, 2019: International Journal of Molecular Sciences
Jonathan Canaani, Myriam Labopin, Maija Itälä-Remes, Didier Blaise, Gerard Socié, Edouard Forcade, Johan Maertens, Depei Wu, Ram Malladi, Jan J Cornelissen, Anne Huynh, Jean Henri Bourhis, Jordi Esteve, Mohamad Mohty, Arnon Nagler
Baseline cytogenetic studies at diagnosis remain the single most important determinant of outcome in patients with acute myeloid leukemia (AML). However, the prognostic role of the complete gamut of cytogenetic aberrations in AML patients undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT) is currently undefined. In addition, their significance in conjunction with FLT3-ITD status has not been addressed thus far. Using the ALWP/EBMT registry we conducted a retrospective analysis to determine the clinical outcomes of AML patients undergoing allo-HSCT with respect to specific recurring cytogenetic abnormalities complemented with FLT3-ITD status...
March 7, 2019: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
Anne Kresinsky, Tina M Schnöder, Ilse D Jacobsen, Martina Rauner, Lorenz C Hofbauer, Volker Ast, Rainer König, Bianca Hoffmann, Carl-Magnus Svensson, Marc Thilo Figge, Ingrid Hilger, Florian H Heidel, Frank- D Böhmer, Jörg P Müller
The receptor tyrosine kinase FLT3 is expressed in myeloid and lymphoid progenitor cells. Activating mutations in FLT3 occur in 25-30% of acute myeloid leukaemia (AML) patients. Most common are internal tandem duplications of sequence (ITD) leading to constitutive FLT3-ITD kinase activity with an altered signalling quality promoting leukaemic cell transformation. Here, we observed the attenuating role of the receptor-like protein tyrosine phosphatase (RPTP) CD45/Ptprc in FLT3 signalling in vivo. Low level expression of this abundant RPTP correlates with a poor prognosis of FLT3-ITD-positive AML patients...
February 28, 2019: Oncogene
Christine A Liang, Lei Chen, Amer Wahed, Andy N D Nguyen
Deep Learning can significantly benefit cancer proteomics and genomics. In this study, we attempted to determine a set of critical proteins that were associated with the FLT3-ITD mutation in newly-diagnosed acute myeloid leukemia patients. A Deep Learning network consisting of autoencoders formed a hierarchical model from which high-level features were extracted without labeled training data. Dimensional reduction reduced the number of critical proteins from 231 to 20. Deep Learning found an excellent correlation between FLT3-ITD mutation with the levels of these 20 critical proteins (accuracy 97%, sensitivity 90%, and specificity 100%)...
January 2019: Annals of Clinical and Laboratory Science
Zhichao Li, Yinmei Liu, Qing Wang, Linjun Chen, Liyuan Ma, Siguo Hao
BACKGROUND: The preferred type of postremission therapy (PRT) for intermediate-risk acute myeloid leukemia (AML) in first complete remission (CR1) is a subject of continued debate. Although allogeneic stem cell transplantation (alloSCT) is regarded as a curative strategy for AML, the efficacy of autologous stem cell transplantation (autoSCT) for patients without a matched sibling donor (MSD) has remained controversial. METHODS: To compare survival outcomes after alloSCT versus autoSCT for patients with intermediate-risk AML in CR1, we performed a meta-analysis of 11 clinical studies...
February 26, 2019: Acta Haematologica
Shahid M Baba, Zafar A Shah, Arshad A Pandith, Dil-Afroze, Aleem Jan, Khurshid A Mir, Sheikh A Aziz, Zahoor Ahmad
AIMS: Distinct types of PML-RARα hybrid transcripts viz bcr-1, bcr-2 and bcr-3 result from translocation between chromosomes 15 and 17 t(15;17) in Acute Promyelocytic Leukemia patients. We aimed to determine the frequencies of the PML-RARα transcripts and FLT3-ITD mutations in APL patients to evaluate their prognostic implications and also to analyze their impact on disease outcome. MAIN METHOD: RT-PCR and Rq-PCR were adopted for transcript typing and quantitation of PML-RARα transcripts while FLT3-ITD was detected by PCR in APL patients...
February 2019: Cancer Genetics
Nicholas J Short, Hagop Kantarjian, Farhad Ravandi, Naval Daver
Mutations in the fms-like tyrosine kinase 3 ( FLT3 ) gene are detected in approximately one-third of patients with newly diagnosed acute myeloid leukemia (AML). These consist of the more common FLT3 -internal tandem duplication (ITD) in approximately 20-25% of AML cases, and point mutations in the tyrosine kinase domain (TKD) in approximately 5-10%. FLT3 mutations, especially FLT3 -ITD, are associated with proliferative disease, increased risk of relapse, and inferior overall survival when treated with conventional regimens...
2019: Therapeutic Advances in Hematology
Xubo Gong, Teng Yu, Qiusu Tang, Yanbiao Fu, Jie Wu, Yongze Zhu, Hongxiang Tu, Haifeng Ge, Xingguo Lu, Donghua Gong, Xiaoying Zhao
INTRODUCTION: AML with inv(3)(q21.3q26.2) or t(3;3)(q21.3;q26.2) [inv(3)/t(3;3)] was very rare. Currently, most reports of AML-inv(3)/t(3;3) were from Western countries, and few reports were from Asian countries. Racial differences in patients with AML-inv(3)/t(3;3) are still unknown. METHODS: Between January 1996 and April 2018, a total of 37 AML cases with inv(3)/t(3;3) were studied retrospectively. They were collected from 2229 primary AML cases performed with conventional cytogenetic analysis (37/2229, 1...
February 22, 2019: International Journal of Laboratory Hematology
Takaaki Konuma, Seiko Kato, Maki Oiwa-Monna, Mai Mizusawa, Masamichi Isobe, Kazuaki Yokoyama, Satoshi Takahashi, Arinobu Tojo
No abstract text is available yet for this article.
February 18, 2019: Leukemia & Lymphoma
Dao-Xing Deng, Hong-Hu Zhu, Yan-Rong Liu, Ying-Jun Chang, Guo-Rui Ruan, Jin-Song Jia, Hao Jiang, Qian Jiang, Xiao-Su Zhao, Xiao-Jun Huang
Acute myeloid leukemia (AML) patients with biallelic CEBPA (bi CEBPA) mutations are considered prognostically favorable, but 38-58% of them still relapse. Therefore, recognizing patients with a high risk of relapse is important. We retrospectively analyzed 83 bi CEBPA AML. Minimal residual disease (MRD) was detected by multiparameter flow cytometry (MFC). Patients with MRD positivity during consolidation chemotherapy had inferior 3-year CIR (55% vs. 36.7%; p = .037) and RFS (45% vs. 63.3%; p = .037) than those with MRD negativity...
February 18, 2019: Leukemia & Lymphoma
Ralf Buettner, Le Xuan Truong Nguyen, Bijender Kumar, Corey Morales, Chao Liu, Lisa S Chen, Tea Pemovska, Timothy W Synold, Joycelynne Palmer, Ryan Thompson, Ling Li, Dinh Hoa Hoang, Bin Zhang, Lucy Ghoda, Claudia Kowolik, Mika Kontro, Calum Leitch, Krister Wennerberg, Xiaochun Xu, Ching-Cheng Chen, David Horne, Varsha Gandhi, Vinod Pullarkat, Guido Marcucci, Steven T Rosen
Nucleoside analogs represent the backbone of several distinct chemotherapy regimens for acute myeloid leukemia (AML) and combination with tyrosine kinase inhibitors has improved survival of AML patients, including those harboring the poor-risk FLT3-ITD mutation. Although these compounds are effective in killing proliferating blasts, they lack activity against quiescent leukemia stem cells (LSCs), which contributes to initial treatment refractoriness or subsequent disease relapse. The reagent 8-chloro-adenosine (8-Cl-Ado) is a ribose-containing, RNA-directed nucleoside analog that is incorporated into newly transcribed RNA rather than in DNA, causing inhibition of RNA transcription...
February 15, 2019: Journal of Cellular Physiology
Sohita Dhillon
Gilteritinib (Xospata® ) is an orally available small molecule receptor tyrosine kinase inhibitor developed by Astellas Pharma in collaboration with Kotobuki Pharmaceutical for the treatment of acute myeloid leukaemia (AML) harbouring FMS-like tyrosine kinase 3 (FLT3) mutations. Gilteritinib inhibits FLT3 (STK1 or FLK2), AXL (UFO or JTK11) and anaplastic lymphoma kinase (ALK or CD246). Gilteritinib inhibits FLT3 signalling in cells expressing FLT3 internal tandem duplication (ITD), tyrosine kinase domain mutation FLT3-D835Y and the double mutant FLT3-ITD-D835Y, thereby inducing apoptosis...
February 5, 2019: Drugs
Lu Tang, Yi-Zhong Peng, Cheng-Gong Li, Hui-Wen Jiang, Heng Mei, Yu Hu
Background: Aberrant miR-155 expression has been reported in various types of hematologic malignancies. However, the prognostic and clinicopathological value of miR-155 remains unclear. Here, we performed this systemic review and meta-analysis to comprehensively evaluate the prognostic and clinicopathological significance of miR-155 expression in hematologic malignancies. Methods: We systematically searched the PubMed, EMBASE, ISI Web of Science, Cochrane library databases and OVID to identify eligible studies published from Jan 1, 2008 to Aug 1, 2018...
2019: Journal of Cancer
Geetanjali R Kamath, Douglas Tremblay, Alexander Coltoff, Jessica Caro, Guido Lancman, Sheena Bhalla, Vesna Najfeld, John Mascarenhas, Emanuela Taioli
Acute promyelocytic leukemia (APL) is a particularly aggressive subtype of acute myeloid leukemia (AML), with high rates of early death. It is important to examine how epidemiologic characteristics, clinical and treatment factors, cytogenetic and genetic data affect survival and differ between APL and non-APL AML patients. We analyzed population data from the New York State Cancer Registry to characterize AML including APL incidence rates by demographics. APL incidence rates were higher among Hispanics than non-Hispanics (Incidence rate ratio=1...
January 23, 2019: Carcinogenesis
Yuan-Yuan Zhang, Xiao-Dong Mo, Xiao-Hui Zhang, Lan-Ping Xu, Yu Wang, Chen-Hua Yan, Huan Chen, Yu-Hong Chen, Wei Han, Feng-Rong Wang, Jing-Zhi Wang, Yu-Qian Sun, Kai-Yan Liu, Xiao-Jun Huang
Acute myelogenous leukemia (AML) patients with fetal liver tyrosine kinase 3 (FLT3) internal tandem duplications (ITDs) have poor prognoses if treated with chemotherapy only, primarily as they experience increased relapse rates. To determine whether this alteration also affects outcomes after haploidentical donor (HID) allogeneic hematopoietic stem cell transplantation (allo-HSCT), we compared 334 consecutive FLT3-ITD-positive vs -negative patients with AML (other than acute promyelocytic leukemia) who underwent HID-HSCT...
February 1, 2019: Bone Marrow Transplantation
Ivan Pasic, Waleed Da'na, Wilson Lam, Arjun Law, Jeffrey H Lipton, Auro Viswabandya, Dennis D Kim, Santhosh Thyagu, Hans A Messner, Fotios V Michelis
OBJECTIVE: In individuals with cytogenetically normal (CN) AML, disease risk is estimated using molecular features such as the status of NPM1 and FLT3-ITD genes. However, data regarding the impact of NPM1 and FLT3-ITD status on hematopoietic stem cell transplant (HCT) outcomes are limited. We examined the effect of NPM1 and FLT3-ITD status on transplant outcomes in 131 CN AML patients transplanted at Princess Margaret Hospital between 2006 and 2017. METHODS: Overall survival (OS) was calculated using Kaplan-Meier analysis and multivariable Cox proportional hazards regression...
January 31, 2019: European Journal of Haematology
Nada Assaf, Jean El-Cheikh, Ali Bazarbachi, Ziad Salem, Chantal Farra, Zaher Chakhachiro, Samer Nassif, Ghazi Zaatari, Rami Mahfouz
Recurrent genetic abnormalities confer distinct morphologic features and play a role in determining the clinical behavior, prognosis and adequate treatment of acute leukemia. In the MENA region, only one study targets the frequency of genetic modifications in AML, reporting a higher occurrence of acute promyelocytic leukemia in Lebanon. Determining the frequency of translocations and gene mutations in acute myeloid and lymphoid leukemia cases in an adult patients' population in Lebanon and comparing the resultant genetic profile with the published international molecular profile of adult acute leukemia...
January 30, 2019: Molecular Biology Reports
Martin Grundy, Sahana Balakrishnan, Matthew Fox, Claire H Seedhouse, Nigel H Russell
Acute myeloid leukaemia (AML) cells often up-regulate pro-survival members of the BCL-2 protein family, such as BCL-2 and MCL-1, to avoid apoptosis. Venetoclax (ABT-199) targets BCL-2 and has shown promising efficacy in AML but over-expression of MCL-1 can cause resistance. A co-operative approach, targeting both BCL-2 and MCL-1 may therefore prove beneficial. This study investigated the potential synergistic relationship between Venetoclax and the MCL-1 inhibitor S63845 in AML cells. We treated MV4-11 cells and primary AML samples for 4 hours with Venetoclax, S63845 or the combination...
December 28, 2018: Oncotarget
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