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https://www.readbyqxmd.com/read/30303964/the-modular-network-structure-of-the-mutational-landscape-of-acute-myeloid-leukemia
#1
Mariam Ibáñez, José Carbonell-Caballero, Esperanza Such, Luz García-Alonso, Alessandro Liquori, María López-Pavía, Marta Llop, Carmen Alonso, Eva Barragán, Inés Gómez-Seguí, Alexander Neef, David Hervás, Pau Montesinos, Guillermo Sanz, Miguel Angel Sanz, Joaquín Dopazo, José Cervera
Acute myeloid leukemia (AML) is associated with the sequential accumulation of acquired genetic alterations. Although at diagnosis cytogenetic alterations are frequent in AML, roughly 50% of patients present an apparently normal karyotype (NK), leading to a highly heterogeneous prognosis. Due to this significant heterogeneity, it has been suggested that different molecular mechanisms may trigger the disease with diverse prognostic implications. We performed whole-exome sequencing (WES) of tumor-normal matched samples of de novo AML-NK patients lacking mutations in NPM1, CEBPA or FLT3-ITD to identify new gene mutations with potential prognostic and therapeutic relevance to patients with AML...
2018: PloS One
https://www.readbyqxmd.com/read/30294391/high-risk-acute-promyelocytic-leukemia-with-unusual-t-myeloid-immunophenotype-successfully-treated-with-atra-and-arsenic-trioxide-based-regimen
#2
Zeba N Singh, Vu H Duong, Rima Koka, Ying Zou, Sameer Sawhney, Li Tang, Maria R Baer, Nicholas Ambulos, Firas El Chaer, Ashkan Emadi
We describe two patients with acute promyelocytic leukemia (APL) with an unusual immunophenotype with co-expression of myeloperoxidase (MPO) with cytoplasmic CD3 (cCD3) representing myeloid and T-lineage differentiation. Both harbored FLT3 -ITD mutations. One additionally had a deletion in the PML gene affecting the primer binding site, thus limiting measurable residual disease (MRD) analysis during follow-up. Both patients achieved durable remission with all-trans retinoic acid (ATRA) and arsenic trioxide (ATO)-based therapy, thus mitigating the need for repetitive conventional chemotherapy cycles and allogeneic stem cell transplantation...
September 2018: Journal of Hematopathology
https://www.readbyqxmd.com/read/30266802/dual-targeting-of-aurora-kinases-with-amg-900-exhibits-potent-preclinical-activity-against-acute-myeloid-leukemia-with-distinct-post-mitotic-outcomes
#3
Marc Payton, Hung-Kam Cheung, Maria Stefania S Ninniri, Christian Marinaccio, William C Wayne, Kelly Hanestad, John D Crispino, Gloria Juan, Angela Coxon
Aurora kinase A and B have essential and non-overlapping roles in mitosis, with elevated expression in a subset of human cancers, including acute myeloid leukemia (AML). In this study, pan-aurora kinase inhibitor (AKI) AMG 900 distinguishes itself as an anti-leukemic agent that is more uniformly potent against a panel of AML cell lines than are isoform-selective AKIs and classic AML drugs. AMG 900 inhibited AML cell growth by inducing polyploidization and/or apoptosis. AMG 900 and aurora-B selective inhibitor AZD1152-hQPA showed comparable cellular effects on AML lines that do not harbor a FLT3-ITD mutation...
September 28, 2018: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/30250637/combination-of-ato-with-flt3-tkis-eliminates-flt3-itd-leukemia-cells-through-reduced-expression-of-flt3
#4
Kozo Nagai, Lihong Hou, Li Li, Bao Nguyen, Tessa Seale, Courtney Shirley, Hayley Ma, Mark Levis, Gabriel Ghiaur, Amy Duffield, Donald Small
Acute myeloid leukemia (AML) patients with FLT3/ITD mutations have a poor prognosis. Monotherapy with selective FLT3 tyrosine kinase inhibitors (TKIs) have shown transient and limited efficacy due to the development of resistance. Arsenic trioxide (ATO, As2 O3 ) has been proven effective in treating acute promyelocytic leukemia (APL) and has shown activity in some cases of refractory and relapsed AML and other hematologic malignances. We explored the feasibility of combining FLT3 TKIs with ATO in the treatment of FLT3/ITD+ leukemias...
August 31, 2018: Oncotarget
https://www.readbyqxmd.com/read/30199909/-aml-in-adults-an-update-on-diagnosis-risk-classification-and-therapy
#5
Karsten Spiekermann, Anne-Sophie Shen
There are several changes in the revised WHO classification for acute leukemia. The latest version of the European Leukemia Network (ELN)-risk classification defines AML with mutations in RUNX1, ASXL1 or TP53 to fall in the unfavorable risk group. Consequently, the somatic molecular genetic testing at the time of initial diagnosis should encompass these before mentioned three genes next to the already routine testing of NPM1, CEBPA and FLT3-ITD. Several new innovative substances have been developed and approved for AML therapy...
September 2018: Deutsche Medizinische Wochenschrift
https://www.readbyqxmd.com/read/30190467/gata2-zinc-finger-1-mutations-are-associated-with-distinct-clinico-biological-features-and-outcomes-different-from-gata2-zinc-finger-2-mutations-in-adult-acute-myeloid-leukemia
#6
Feng-Ming Tien, Hsin-An Hou, Cheng-Hong Tsai, Jih-Luh Tang, Yu-Chiao Chiu, Chien-Yuan Chen, Yuan-Yeh Kuo, Mei-Hsuan Tseng, Yen-Ling Peng, Ming-Chih Liu, Chia-Wen Liu, Xiu-Wen Liao, Liang-In Lin, Chien-Ting Lin, Shang-Ju Wu, Bor-Sheng Ko, Szu-Chun Hsu, Shang-Yi Huang, Ming Yao, Wen-Chien Chou, Hwei-Fang Tien
Mutations of the GATA binding protein 2 (GATA2) gene in myeloid malignancies usually cluster in the zinc finger 1 (ZF1) and the ZF2 domains. Mutations in different locations of GATA2 may have distinct impact on clinico-biological features and outcomes in AML patients, but little is known in this aspect. In this study, we explored GATA2 mutations in 693 de novo non-M3 AML patients and identified 44 GATA2 mutations in 43 (6.2%) patients, including 31 in ZF1, 10 in ZF2, and three outside the two domains. Different from GATA2 ZF2 mutations, ZF1 mutations were closely associated with French-American-British (FAB) M1 subtype, CEBPA double mutations (CEBPAdouble-mut ), but inversely correlated with FAB M4 subtype, NPM1 mutations, and FLT3-ITD...
August 31, 2018: Blood Cancer Journal
https://www.readbyqxmd.com/read/30190321/measurable-residual-disease-mrd-monitoring-by-ngs-before-allogeneic-hematopoietic-cell-transplantation-in-aml
#7
Felicitas Thol, Razif Gabdoulline, Alessandro Liebich, Piroska Klement, Johannes Schiller, Christian Kandziora, Lothar Hambach, Michael Stadler, Christian Koenecke, Madita Flintrop, Mira Pankratz, Martin Wichmann, Blerina Neziri, Konstantin Büttner, Bennet Heida, Sabrina Klesse, Anuhar Chaturvedi, Arnold Kloos, Gudrun Göhring, Brigitte Schlegelberger, Verena I Gaidzik, Lars Bullinger, Walter Fiedler, Albert Heim, Iyas Hamwi, Matthias Eder, Jürgen Krauter, Richard F Schlenk, Peter Paschka, Konstanze Döhner, Hartmut Döhner, Arnold Ganser, Michael Heuser
Molecular measurable residual disease (MRD) assessment is not established in approximately 60 percent of acute myeloid leukemia (AML) patients due to the lack of suitable markers for quantitative real-time PCR. To overcome this limitation we established an error-corrected next-generation-sequencing (NGS) MRD approach which can be applied to any somatic gene mutation. The clinical significance of this approach was evaluated in 116 AML patients undergoing allogeneic hematopoietic cell transplantation (alloHCT) in complete morphologic remission (CR)...
September 6, 2018: Blood
https://www.readbyqxmd.com/read/30181385/classes-of-itd-predict-outcomes-in-aml-patients-treated-with-flt3-inhibitors
#8
Gregory W Schwartz, Bryan S Manning, Yeqiao Zhou, Priya D Velu, Ashkan Bigdeli, Rachel Astles, Anne W Lehman, Jennifer Jd Morrissette, Alexander E Perl, Mingyao Li, Martin Carroll, Robert Babak Faryabi
PURPOSE: Recurrent internal tandem duplication (ITD) mutations are observed in various cancers including acute myeloid leukemia (AML), where ITD mutations in tyrosine kinase receptor FLT3 are associated with poor prognostic outcomes. Several FLT3 inhibitors (FLT3i) are in clinical trials for high-risk FLT3 -ITD-positive AML. However, the variability of survival following FLT3i treatment suggests that the mere presence of FLT3 -ITD mutations might not guarantee effective clinical response...
September 4, 2018: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/30180463/-outcome-of-acute-myeloid-leukemia-with-flt3-itd-mutation-treated-by-allogeneic-hematopoietic-stem-cell-transplantation
#9
C Liang, E L Jiang, J F Yao, Y He, R L Zhang, D L Yang, Q L Ma, W H Zhai, Y Huang, J L Wei, S Z Feng, M Z Han
Objective: To evaluate the efficacy of allogeneic hematopoietic stem cell transplantation (allo-HSCT) for the treatment of acute myeloid leukemia (AML) patients with FLT3-ITD mutation. Methods: From September 2008 to December 2016, 40 AML patients with FLT3-ITD mutation were enrolled in the study. The therapeutic process, outcomes and prognostic factors were retrospectively analyzed. Results: The median of WBC at initial diagnosis was 35.0 (range 1.7-185.0) ×10(9)/L. The median course number of chemotherapy was 4 (range 2-7)...
August 14, 2018: Zhonghua Xue Ye Xue za Zhi, Zhonghua Xueyexue Zazhi
https://www.readbyqxmd.com/read/30159298/absence-of-flt3-mutations-in-iranian-adult-t-cell-leukemia-lymphoma-patients
#10
Hossein Ayatollahi, Mohammadhadi Sadeghian, Mohammadmahdi Kooshyar, Abass Shirdel, Hossein Rahimi, Amirhossein Jafarian, Saeide Ghazaei, Narges Soltani, Fatemeh Shams, Neda Motamedi Rad, Sepideh Shakeri
Background: Adult T cell leukemia lymphoma (ATLL) is a rare disease, significantly linked to the infection by the human T-cell lymphotropic virus 1(HTLV-1). ATLL is typically preceded by decades of clinical latency during which infected cells accumulate selectable traits leading to a malignant transformation. Amongst all the HTLV-1 infected carriers only about 3-5% will develop ATLL. Despite the intensive attempt to improve the overall survival, ATLL remains one of worse prognosis among the hematologic malignancies...
2018: Medical Journal of the Islamic Republic of Iran
https://www.readbyqxmd.com/read/30147364/use-of-flt3-inhibitors-in-acute-myeloid-leukemia-remission-induction-or-salvage-therapy-systematic-review-and-meta-analysis
#11
Minglei Yang, Jian Zhao, Tielong Liu, Xinghai Yang, Haifeng Wei, Wei Xu, Jianru Xiao
Background: Previous studies showed that FLT3 inhibitors played an important role in acute myeloid leukemia (AML) therapy. However, discrepancies remain regarding the association between FLT3 inhibitors use and prognosis of AML patients in clinical trials. Aim: The aim of this study was to evaluate the effect of FLT3 inhibitors on the treatment of AML in a systematic review and meta-analysis. Materials and methods: PubMed, Embase, and Cochrane Library databases were searched for studies published before August 2017 that used FLT3 inhibitors in AML...
2018: Cancer Management and Research
https://www.readbyqxmd.com/read/30122998/biological-and-clinical-influences-of-npm1-in-acute-myeloid-leukemia-patients-with-dnmt3a-mutations
#12
Xinrui Yang, Jinlong Shi, Xinpei Zhang, Gaoqi Zhang, Jilei Zhang, Siyuan Yang, Jing Wang, Xiaoyan Ke, Lin Fu
Purpose: DNMT3A and NPM1 mutations are known to impact the prognosis of acute myeloid leukemia (AML). DNMT3A mutations are negative prognostic factors, while NPM1 mutations are low-risk factors and inclined to concurrently appear with DNMT3A mutations. In this study, we aimed to find out how NPM1 mutations affect patients' outcomes in the background of DNMT3A mutations. Patients and methods: We screened The Cancer Genome Atlas (TCGA) database and found 51 AML patients with DNMT3A mutations...
2018: Cancer Management and Research
https://www.readbyqxmd.com/read/30122013/-effect-of-flt3-itd-with-dnmt3a-r882-double-mutation-on-the-prognosis-of-acute-myeloid-leukemia-after-allogeneic-hematopoietic-stem-cell-transplantation
#13
S H Tang, Y Lu, P S Zhang, X H Liu, X H Du, D Chen, K Y Sha, S Y Li, J J Cao, L G Chen, X X Zhuang, R Z Pei, X W Tang
Objective: To investigate the impact of FLT3-ITD and DNMT3A R882 double mutations to the prognosis of acute myeloid leukemia after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Methods: FLT3-ITD, DNMT3A, C-kit, CEBPA, FLT3-TKD and NPM1 mutations were detected in 206 newly diagnosed AML patients by Sanger sequencing (M(3) and those received FLT3 inhibitor were excluded). Clinical data of AML patients were retrospectively analyzed to compare the prognosis of each gene mutation group. Results: ①Of 206 patients, 104 were male and 102 female with a median age of 38 (3-63) years, including 6 cases of M(0), 24 cases of M(1), 56 cases of M(2), 39 cases of M(4), 63 cases of M(5), 6 cases of M(6) and 12 unclassified cases...
July 14, 2018: Zhonghua Xue Ye Xue za Zhi, Zhonghua Xueyexue Zazhi
https://www.readbyqxmd.com/read/30102945/epigenetic-modification-enhances-the-cytotoxicity-of-busulfan-and4-hydroperoxycyclophosphamide-in-aml-cells
#14
Benigno C Valdez, Xiaowen Tang, Yang Li, David Murray, Yan Liu, Uday Popat, Richard E Champlin, Borje S Andersson
The combination of the DNA-alkylating agents busulfan (Bu) and cyclophosphamide is the most commonly used myeloablative pretransplantation conditioning therapy for myeloid leukemias. However, it is associated with significant nonrelapse mortality, which prohibits dose escalation to control relapse. We hypothesized that combining these two drugs with an epigenetic modifier would increase antileukemic efficacy without jeopardizing patient safety. A preclinical study was performed to determine the synergistic cytotoxicity of Bu, 4-hydroperoxycyclophosphamide (4HC), and the hypomethylating agent decitabine (DAC) in human acute myeloid leukemia (AML) cell lines...
August 10, 2018: Experimental Hematology
https://www.readbyqxmd.com/read/30089730/foxm1-contributes-to-treatment-failure-in-acute-myeloid-leukemia
#15
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
https://www.readbyqxmd.com/read/30082225/flt3-tkd-mutations-associated-with-npm1-mutations-define-a-favorable-risk-group-in-patients-with-acute-myeloid-leukemia
#16
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
https://www.readbyqxmd.com/read/30082223/wilms-tumor-1-expression-at-diagnosis-correlates-with-genetic-abnormalities-and-polymorphism-but-is-not-independently-prognostic-in-acute-myelogenous-leukemia-a-hokkaido-leukemia-net-study
#17
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
https://www.readbyqxmd.com/read/30076182/impact-of-flt3-itd-length-on-prognosis-of-acute-myeloid-leukemia
#18
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
https://www.readbyqxmd.com/read/30064973/genetic-and-epigenetic-evolution-as-a-contributor-to-wt1-mutant-leukemogenesis
#19
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 Wilms' tumor 1 ( WT1 ) 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...
September 20, 2018: Blood
https://www.readbyqxmd.com/read/30046393/clonal-heterogeneity-of-flt3-itd-detected-by-high-throughput-amplicon-sequencing-correlates-with-adverse-prognosis-in-acute-myeloid-leukemia
#20
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
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