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https://www.readbyqxmd.com/read/29661468/successful-treatment-of-cytogenetically-normal-acute-myeloid-leukemia-with-ten-eleven-translocation-2-isocitrate-dehydrogenase-2-and-additional-sex-comb-like-1-nucleophosmin-co-mutations-by-hla-haploidentical-stem-cell-transplantation-a-case-report-and-literature
#1
Y Liu, Y Cao, Y Lin, W-M Dong, R-R Lin, Q Gu, X-B Xie, W-Y Gu
The presence of recurrent gene mutations is increasingly important in acute myeloid leukemia (AML) and sheds new insights into the understanding of leukemogenesis, prognostic evaluation, and clinical therapeutic efficacy. Until now, ten-eleven translocation 2 (TET2) and isocitrate dehydrogenase 2 (IDH2) mutations were reported to be mutually exclusive in AML patients. Similarly, nucleophosmin (NPM1) and additional sex comb-like 1 (ASXL1) mutations were rarely coexisted in AML. A 47-year-old man diagnosed with high-risk AML presented simultaneous mutations of TET2-IDH2 and NPM1-ASXL1 revealed by next-generation sequencing...
April 2018: Transplantation Proceedings
https://www.readbyqxmd.com/read/29643185/expression-of-mutant-asxl1-perturbs-hematopoiesis-and-promotes-susceptibility-to-leukemic-transformation
#2
Reina Nagase, Daichi Inoue, Alessandro Pastore, Takeshi Fujino, Hsin-An Hou, Norimasa Yamasaki, Susumu Goyama, Makoto Saika, Akinori Kanai, Yasuyuki Sera, Sayuri Horikawa, Yasunori Ota, Shuhei Asada, Yasutaka Hayashi, Kimihito Cojin Kawabata, Reina Takeda, Hwei-Fang Tien, Hiroaki Honda, Omar Abdel-Wahab, Toshio Kitamura
Additional sex combs like 1 ( ASXL1 ) is frequently mutated in myeloid malignancies and clonal hematopoiesis of indeterminate potential (CHIP). Although loss of ASXL1 promotes hematopoietic transformation, there is growing evidence that ASXL1 mutations might confer an alteration of function. In this study, we identify that physiological expression of a C-terminal truncated Asxl1 mutant in vivo using conditional knock-in (KI) results in myeloid skewing, age-dependent anemia, thrombocytosis, and morphological dysplasia...
April 11, 2018: Journal of Experimental Medicine
https://www.readbyqxmd.com/read/29619748/association-of-gene-mutations-with-response-to-arsenic-containing-compound-qinghuang-powder-in-patients-with-myelodysplastic-syndromes
#3
Pan Zhao, Jun-Bin Liang, Zhong-Yang Deng, Ming-Jing Wang, Jia-Yue Qin, Chong-Jian Chen, Xiao-Mei Hu
OBJECTIVES: To investigate the relationship between gene mutations and response to Compound Qinghuang Powder (, CQHP) in patients with myelodysplastic syndrome (MDS). METHODS: Forty-three MDS patients were genotyped by ultra-deep targeted sequencing and the clinical data of patients were collected and the relationship between them was analyzed. RESULTS: Up to 41.86% of patients harbored genet mutations, in most cases with more than one mutation...
April 4, 2018: Chinese Journal of Integrative Medicine
https://www.readbyqxmd.com/read/29618722/incorporation-of-mutations-in-five-genes-in-the-revised-international-prognostic-scoring-system-can-improve-risk-stratification-in-the-patients-with-myelodysplastic-syndrome
#4
Hsin-An Hou, Cheng-Hong Tsai, Chien-Chin Lin, Wen-Chien Chou, Yuan-Yeh Kuo, Chieh-Yu Liu, Mei-Hsuan Tseng, Yen-Ling Peng, Ming-Chih Liu, Chia-Wen Liu, Xiu-Wen Liao, Liang-In Lin, Ming Yao, Jih-Luh Tang, Hwei-Fang Tien
Gene mutations have not yet been included in the 2016 WHO classification and revised International Prognostic Scoring System (IPSS-R), which are now widely utilized to discriminate myelodysplastic syndrome (MDS) patients regarding risk of leukemia evolution and overall survival (OS). In this study, we aimed to investigate whether integration of gene mutations with other risk factors could further improve the stratification of MDS patients. Mutational analyses of 25 genes relevant to myeloid malignancies in 426 primary MDS patients showed that mutations of CBL, IDH2, ASXL1, DNMT3A, and TP53 were independently associated with shorter survival...
April 4, 2018: Blood Cancer Journal
https://www.readbyqxmd.com/read/29601269/molecular-minimal-residual-disease-in-acute-myeloid-leukemia
#5
Mojca Jongen-Lavrencic, Tim Grob, Diana Hanekamp, François G Kavelaars, Adil Al Hinai, Annelieke Zeilemaker, Claudia A J Erpelinck-Verschueren, Patrycja L Gradowska, Rosa Meijer, Jacqueline Cloos, Bart J Biemond, Carlos Graux, Marinus van Marwijk Kooy, Markus G Manz, Thomas Pabst, Jakob R Passweg, Violaine Havelange, Gert J Ossenkoppele, Mathijs A Sanders, Gerrit J Schuurhuis, Bob Löwenberg, Peter J M Valk
BACKGROUND: Patients with acute myeloid leukemia (AML) often reach complete remission, but relapse rates remain high. Next-generation sequencing enables the detection of molecular minimal residual disease in virtually every patient, but its clinical value for the prediction of relapse has yet to be established. METHODS: We conducted a study involving patients 18 to 65 years of age who had newly diagnosed AML. Targeted next-generation sequencing was carried out at diagnosis and after induction therapy (during complete remission)...
March 29, 2018: New England Journal of Medicine
https://www.readbyqxmd.com/read/29556021/a-novel-asxl1-ogt-axis-plays-roles-in-h3k4-methylation-and-tumor-suppression-in-myeloid-malignancies
#6
Daichi Inoue, Takeshi Fujino, Paul Sheridan, Yao-Zhong Zhang, Reina Nagase, Sayuri Horikawa, Zaomin Li, Hirotaka Matsui, Akinori Kanai, Makoto Saika, Rui Yamaguchi, Hiroko Kozuka-Hata, Kimihito Cojin Kawabata, Akihiko Yokoyama, Susumu Goyama, Toshiya Inaba, Seiya Imoto, Satoru Miyano, Mingjiang Xu, Feng-Chun Yang, Masaaki Oyama, Toshio Kitamura
ASXL1 plays key roles in epigenetic regulation of gene expression through methylation of histone H3K27, and disruption of ASXL1 drives myeloid malignancies, at least in part, via derepression of posterior HOXA loci. However, little is known about the identity of proteins that interact with ASXL1 and about the functions of ASXL1 in modulation of the active histone mark, such as H3K4 methylation. In this study, we demonstrate that ASXL1 is a part of a protein complex containing HCFC1 and OGT; OGT directly stabilizes ASXL1 by O-GlcNAcylation...
March 3, 2018: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
https://www.readbyqxmd.com/read/29532865/crispr-cas9-mediated-asxl1-mutations-in-u937-cells-disrupt-myeloid-differentiation
#7
Zhi-Jie Wu, Xin Zhao, Lauren G Banaszak, Fernanda Gutierrez-Rodrigues, Keyvan Keyvanfar, Shou-Guo Gao, Diego Quinones Raffo, Sachiko Kajigaya, Neal S Young
Additional sex combs-like 1 (ASXL1) is a well‑known tumor suppressor gene and epigenetic modifier. ASXL1 mutations are frequent in myeloid malignances; these mutations are risk factors for the development of myelodysplasia and also appear as small clones during normal aging. ASXL1 appears to act as an epigenetic regulator of cell survival and myeloid differentiation; however, the molecular mechanisms underlying the malignant transformation of cells with ASXL1 mutations are not well defined. Using Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)/CRISPR-associated protein-9 nuclease (Cas9) genome editing, heterozygous and homozygous ASXL1 mutations were introduced into human U937 leukemic cells...
April 2018: International Journal of Oncology
https://www.readbyqxmd.com/read/29515238/philadelphia-chromosome-negative-classical-myeloproliferative-neoplasms-revised-management-recommendations-from-european-leukemianet
#8
REVIEW
Tiziano Barbui, Ayalew Tefferi, Alessandro M Vannucchi, Francesco Passamonti, Richard T Silver, Ronald Hoffman, Srdan Verstovsek, Ruben Mesa, Jean-Jacques Kiladjian, Rȕdiger Hehlmann, Andreas Reiter, Francisco Cervantes, Claire Harrison, Mary Frances Mc Mullin, Hans Carl Hasselbalch, Steffen Koschmieder, Monia Marchetti, Andrea Bacigalupo, Guido Finazzi, Nicolaus Kroeger, Martin Griesshammer, Gunnar Birgegard, Giovanni Barosi
This document updates the recommendations on the management of Philadelphia chromosome-negative myeloproliferative neoplasms (Ph-neg MPNs) published in 2011 by the European LeukemiaNet (ELN) consortium. Recommendations were produced by multiple-step formalized procedures of group discussion. A critical appraisal of evidence by using Grades of Recommendation, Assessment, Development and Evaluation (GRADE) methodology was performed in the areas where at least one randomized clinical trial was published. Seven randomized controlled trials provided the evidence base; earlier phase trials also informed recommendation development...
February 27, 2018: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
https://www.readbyqxmd.com/read/29515114/momelotinib-therapy-for-myelofibrosis-a-7-year-follow-up
#9
Ayalew Tefferi, Daniela Barraco, Terra L Lasho, Sahrish Shah, Kebede H Begna, Aref Al-Kali, William J Hogan, Mark R Litzow, Curtis A Hanson, Rhett P Ketterling, Naseema Gangat, Animesh Pardanani
One-hundred Mayo Clinic patients with high/intermediate-risk myelofibrosis (MF) received momelotinib (MMB; JAK1/2 inhibitor) between 2009 and 2010, as part of a phase 1/2 trial (NCT00935987); 73% harbored JAK2 mutations, 16% CALR, 7% MPL, 44% ASXL1, and 18% SRSF2. As of July 2017, MMB was discontinued in 91% of the patients, after a median treatment duration of 1.4 years. Grade 3/4 toxicity included thrombocytopenia (34%) and liver/pancreatic test abnormalities (<10%); grade 1/2 peripheral neuropathy occurred in 47%...
March 7, 2018: Blood Cancer Journal
https://www.readbyqxmd.com/read/29512199/chronic-neutrophilic-leukemia-2018-update-on-diagnosis-molecular-genetics-and-management
#10
Michelle A Elliott, Ayalew Tefferi
DISEASE OVERVIEW AND DIAGNOSIS: Chronic neutrophilic leukemia (CNL) is a potentially aggressive myeloproliferative neoplasm, for which current WHO diagnostic criteria include leukocytosis of ≥ 25 x 109 /L of which ≥ 80% are neutrophils, with < 10% circulating neutrophil precursors with blasts rarely observed. In addition, there is no dysplasia, nor clinical or molecular criteria for other myeloproliferative neoplasms. UPDATE ON DIAGNOSIS: Previously the diagnosis of CNL was often as one of exclusion based on no identifiable cause for physiologic neutrophilia in patients fulfilling the aforementioned criteria...
August 2018: American Journal of Hematology
https://www.readbyqxmd.com/read/29472724/persistence-of-pre-leukemic-clones-during-first-remission-and-risk-of-relapse-in-acute-myeloid-leukemia
#11
Maja Rothenberg-Thurley, Susanne Amler, Dennis Goerlich, Thomas Köhnke, Nikola P Konstandin, Stephanie Schneider, Maria C Sauerland, Tobias Herold, Max Hubmann, Bianka Ksienzyk, Evelyn Zellmeier, Stefan K Bohlander, Marion Subklewe, Andreas Faldum, Wolfgang Hiddemann, Jan Braess, Karsten Spiekermann, Klaus H Metzeler
Some patients with acute myeloid leukemia (AML) who are in complete remission after induction chemotherapy harbor persisting pre-leukemic clones, carrying a subset of leukemia-associated somatic mutations. There is conflicting evidence on the prognostic relevance of these clones for AML relapse. Here, we characterized paired pre-treatment and remission samples from 126 AML patients for mutations in 68 leukemia-associated genes. Fifty patients (40%) retained ≥1 mutation during remission at a VAF of ≥2%. Mutation persistence was most frequent in DNMT3A (65% of patients with mutations at diagnosis), SRSF2 (64%), TET2 (55%), and ASXL1 (46%), and significantly associated with older age (p < 0...
February 23, 2018: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
https://www.readbyqxmd.com/read/29472717/revised-cytogenetic-risk-stratification-in-primary-myelofibrosis-analysis-based-on-1002-informative-patients
#12
Ayalew Tefferi, Maura Nicolosi, Mythri Mudireddy, Terra L Lasho, Naseema Gangat, Kebede H Begna, Curtis A Hanson, Rhett P Ketterling, Animesh Pardanani
Current cytogenetic risk stratification in primary myelofibrosis (PMF) is two-tiered: 'favorable' and 'unfavorable'. Recent studies have suggested prognostic heterogeneity within the unfavorable risk category. In 1002 consecutive patients, we performed stepwise analysis of impact on survival from individual and prognostically ordered cytogenetic abnormalities, leading to a revised three-tiered risk model: 'very high risk (VHR)'-single/multiple abnormalities of -7, i(17q), inv(3)/3q21, 12p-/12p11.2, 11q-/11q23, or other autosomal trisomies not including + 8/ + 9 (e...
February 2, 2018: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
https://www.readbyqxmd.com/read/29467191/targeted-next-generation-sequencing-in-blast-phase-myeloproliferative-neoplasms
#13
Terra L Lasho, Mythri Mudireddy, Christy M Finke, Curtis A Hanson, Rhett P Ketterling, Natasha Szuber, Kebede H Begna, Mrinal M Patnaik, Naseema Gangat, Animesh Pardanani, Ayalew Tefferi
Among 248 consecutive patients with blast phase myeloproliferative neoplasm (MPN-BP), DNA collected at the time of blast transformation was available in 75 patients (median age, 66 years; 64% men). MPN-BP followed primary myelofibrosis in 39 patients, essential thrombocythemia in 20 patients, and polycythemia vera in 16 patients. A myeloid neoplasm-relevant 33-gene panel was used for next-generation sequencing. Driver mutation distribution was JAK2 57%, CALR 20%, MPL 9%, and triple-negative 13%. Sixty-four patients (85%) harbored other mutations/variants, including 37% with ≥3 mutations; most frequent were ASXL1 47%, TET2 19%, RUNX1 17%, TP53 16%, EZH2 15%, and SRSF2 13%; relative mutual exclusivity was expressed by TP53 , EZH2 , LNK , RUNX1 , SRSF2 , and NRAS/KRAS mutations...
February 27, 2018: Blood Advances
https://www.readbyqxmd.com/read/29456859/acute-myeloid-leukemia-in-a-father-and-son-with-a-germline-mutation-of-asxl1
#14
Karen Seiter, Kyaw Htun, Paul Baskind, Zach Liu
Background: Myelodysplastic syndromes and acute myeloid leukemia usually occur sporadically in older adults. More recently cases of familial acute myeloid leukemia and/or myelodysplastic syndrome have been reported. Case presentation: Currently we report a father and son who both developed myelodysplastic syndrome that progressed to acute myeloid leukemia. Both patients were found to have the identical mutation of ASXL1 on nextgen sequencing of both hematologic and nonhematologic tissues...
2018: Biomarker Research
https://www.readbyqxmd.com/read/29427188/molecular-characteristic-of-acute-leukemias-with-t-16-21-fus-erg
#15
Elena Zerkalenkova, Agnesa Panfyorova, Anna Kazakova, Pavel Baryshev, Larisa Shelihova, Irina Kalinina, Galina Novichkova, Michael Maschan, Aleksey Maschan, Yulia Olshanskaya
T(16;21)(p11;q22)/FUS-ERG is a rare but recurrent translocation in acute leukemias and in some types of solid tumors. Due to multiple types of FUS-ERG transcripts, PCR-based minimal residual disease detection is impeded. In this study, we evaluated a cohort of pediatric patients with t(16;21)(p11;q22)/FUS-ERG and revealed fusion gene breakpoints. We implemented next-generation sequencing (NGS) on long PCR amplicons for the detection of fusion genes with unknown partners or DNA breakpoints. That allowed us to describe different fusion variants of FUS/ERG in different patients and to detect MRD on both RNA and DNA levels...
February 9, 2018: Annals of Hematology
https://www.readbyqxmd.com/read/29423272/loss-of-asxl1-in-the-bone-marrow-niche-dysregulates-hematopoietic-stem-and-progenitor-cell-fates
#16
Peng Zhang, Zizhen Chen, Rong Li, Ying Guo, Hui Shi, Jie Bai, Hui Yang, Mengyao Sheng, Zhaomin Li, Zhuo Li, Jianping Li, Shi Chen, Weiping Yuan, Tao Cheng, Mingjiang Xu, Yuan Zhou, Feng-Chun Yang
Somatic or de novo mutations of Additional sex combs-like 1 ( ASXL1 ) frequently occur in patients with myeloid malignancies or Bohring-Opitz syndrome, respectively. We have reported that global loss of Asxl1 leads to the development of myeloid malignancies and impairs bone marrow stromal cell (BMSC) fates in mice. However, the impact of Asxl1 deletion in the BM niche on hematopoiesis remains unclear. Here, we showed that BMSCs derived from chronic myelomonocytic leukemia patients had reduced expression of ASXL1 , which impaired the maintaining cord blood CD34+ cell colony-forming capacity with a myeloid differentiation bias...
2018: Cell Discovery
https://www.readbyqxmd.com/read/29417633/mutations-and-prognosis-in-myelodysplastic-syndromes-karyotype-adjusted-analysis-of-targeted-sequencing-in-300-consecutive-cases-and-development-of-a-genetic-risk-model
#17
Naseema Gangat, Mythri Mudireddy, Terra L Lasho, Christy M Finke, Maura Nicolosi, Natasha Szuber, Mrinal M Patnaik, Animesh Pardanani, Curtis A Hanson, Rhett P Ketterling, Ayalew Tefferi
In order to develop a genetic risk model for primary myelodysplastic syndromes (MDS), we queried the prognostic significance of next-generation sequencing (NGS)-derived mutations, in the context of the Mayo cytogenetic risk stratification, which includes high-risk (monosomal karyotype; MK), intermediate-risk (non-MK, classified as intermediate/poor/very poor, per the revised international prognostic scoring system; IPSS-R), and low-risk (classified as good/very good, per IPSS-R). Univariate analysis in 300 consecutive patients with primary MDS identified TP53, RUNX1, U2AF1, ASXL1, EZH2 and SRSF2 mutations as "unfavorable" and SF3B1 as "favorable" risk factors for survival; for the purposes of the current study, the absence of SF3B1 mutation was accordingly dubbed as an "adverse" mutation...
February 8, 2018: American Journal of Hematology
https://www.readbyqxmd.com/read/29417354/clonal-dynamics-in-a-case-of-acute-monoblastic-leukemia-that-later-developed-myeloproliferative-neoplasm
#18
Shinya Sato, Hidehiro Itonaga, Masataka Taguchi, Yasushi Sawayama, Daisuke Imanishi, Hideki Tsushima, Tomoko Hata, Yukiyoshi Moriuchi, Hiroyuki Mishima, Akira Kinoshita, Koh-Ichiro Yoshiura, Yasushi Miyazaki
In acute myeloid leukemia (AML), patients may harbor pre-leukemic hematopoietic stem cells (HSCs) containing some, but not all, of the mutations observed in the leukemic cells. These pre-leukemic HSCs may survive induction chemotherapy and contribute to AML relapse by obtaining additional mutations. We report here an acute monoblastic leukemia (AMoL) patient who later developed an unclassifiable myeloproliferative neoplasm (MPN-U). Whole-exome sequencing and cluster analysis demonstrated the presence of three distinct major clones during the clinical course: (1) an AMoL clone with ASXL1, CBL, and NPM1 somatic mutations, likely associated with the pathogenesis, and GATA2, SRSF2, and TET2 mutations, (2) an AMoL remission clone, with mutated GATA2, SRSF2, and TET2 only (possibly the founding clone (pre-leukemic HSC) that survived chemotherapy), (3) a small subclone which had JAK2 mutation during the AMoL remission, appearing at MPN-U manifestation with additional mutations...
February 7, 2018: International Journal of Hematology
https://www.readbyqxmd.com/read/29411666/asxl1-mutations-in-aml-are-associated-with-specific-clinical-and-cytogenetic-characteristics
#19
Katerina Kakosaiou, Fotios Panitsas, Aggeliki Daraki, Maria Pagoni, Paraskevi Apostolou, Agapi Ioannidou, Ioanna Vlachadami, Theodoros Marinakis, Chara Giatra, Diamantina Vasilatou, Constantina Sambani, Vassiliki Pappa, Kalliopi N Manola
Mutations of ASXL1 are early events in acute myeloid leukemia (AML) leukemogenesis and have been associated with unfavorable prognosis. In this study, we investigated the type and frequency of ASXL1 mutations in a large cohort of patients with de novo or secondary AML (s-AML) and looked for correlations with cytogenetic findings and disease features. ASXL1 mutations were associated with older age, s-AML and higher peripheral leukocytosis. We observed more frequent co-occurrence of ASXL1 mutations with trisomy 8 and chromosome 11 aberrations but a negative correlation with myelodysplastic syndromes (MDS)-related cytogenetic abnormalities, especially -5/del(5q) and -7/del(7q)...
February 7, 2018: Leukemia & Lymphoma
https://www.readbyqxmd.com/read/29383137/polycomb-protein-ring1a-limits-hematopoietic-differentiation-in-myelodysplastic-syndromes
#20
Anna Palau, Anne-Kathrin Garz, Jeannine Diesch, Anabel Zwick, Roberto Malinverni, Vanesa Valero, Katrina Lappin, Raquel Casquero, Andreas Lennartsson, Johannes Zuber, Tomàs Navarro, Ken I Mills, Katharina S Götze, Marcus Buschbeck
Genetic lesions affecting epigenetic regulators are frequent in myelodysplastic syndromes (MDS). Polycomb proteins are key epigenetic regulators of differentiation and stemness that act as two multimeric complexes termed polycomb repressive complexes 1 and 2, PRC1 and PRC2, respectively. While components and regulators of PRC2 such as ASXL1 and EZH2 are frequently mutated in MDS and AML, little is known about the role of PRC1. To analyze the role of PRC1, we have taken a functional approach testing PRC1 components in loss- and gain-of-function experiments that we found overexpressed in advanced MDS patients or dynamically expressed during normal hematopoiesis...
December 29, 2017: Oncotarget
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