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leukemia genomic

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https://www.readbyqxmd.com/read/28230820/the-distribution-of-tp53-gene-polymorphisms-in-chronic-lymphocytic-leukemia-patients-sufferers-of-chornobyl-nuclear-power-plant-accident
#1
N I Bilous, I V Abramenko, A A Chumak, I S Dyagil, Z V Martina
: Previous analyses in a cohort of Chornobyl cleanup workers revealed significantly increased radiation-related risk for all leukemia types, including chronic lymphocytic leukemia (CLL). Numerous investigations emphasized the significance of genetic susceptibility to the radiation carcinogenesis. The aim of the work was to study the distribution of TP53 single nucleotide polymorphisms (SNPs) in CLL patients exposed to ionizing radiation (IR) due to Chornobyl nuclear power plant accident and estimate their impact on disease development...
December 2016: Experimental Oncology
https://www.readbyqxmd.com/read/28223820/flt3-inhibitors-clinical-potential-in-acute-myeloid-leukemia
#2
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
#3
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/28215704/cpg-island-hypermethylation-mediated-by-dnmt3a-is-a-consequence-of-aml-progression
#4
David H Spencer, David A Russler-Germain, Shamika Ketkar, Nichole M Helton, Tamara L Lamprecht, Robert S Fulton, Catrina C Fronick, Michelle O'Laughlin, Sharon E Heath, Marwan Shinawi, Peter Westervelt, Jacqueline E Payton, Lukas D Wartman, John S Welch, Richard K Wilson, Matthew J Walter, Daniel C Link, John F DiPersio, Timothy J Ley
DNMT3A mutations occur in ∼25% of acute myeloid leukemia (AML) patients. The most common mutation, DNMT3A(R882H), has dominant negative activity that reduces DNA methylation activity by ∼80% in vitro. To understand the contribution of DNMT3A-dependent methylation to leukemogenesis, we performed whole-genome bisulfite sequencing of primary leukemic and non-leukemic cells in patients with or without DNMT3A(R882) mutations. Non-leukemic hematopoietic cells with DNMT3A(R882H) displayed focal methylation loss, suggesting that hypomethylation antedates AML...
February 13, 2017: Cell
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/28214593/jak-stat-pathway-directed-therapy-of-t-cell-leukemia-lymphoma-inspired-by-functional-and-structural-genomics
#6
REVIEW
Thomas A Waldmann
Abnormal activation of the γc cytokine JAK/STAT signaling pathway assessed by STAT3 or STAT5b phosphorylation was present in a proportion of many T-cell malignancies. Activating mutations of STAT3/STAT5b and JAK1/3 were present in some but not in all cases with constitutive signaling pathway activation. Using shRNA analysis pSTAT malignant T-cell lines were addicted to JAKs/STATs whether they were mutated or not. Activating JAK/STAT mutations were not sufficient to support leukemic cell proliferation but only augmented upstream pathway signals...
February 15, 2017: Molecular and Cellular Endocrinology
https://www.readbyqxmd.com/read/28212528/the-crispr-cas9%C3%A2-system-efficiently-reverts-the-tumorigenic-ability-of-bcr-abl-in-vitro-and-in-a-xenograft-model-of-chronic-myeloid-leukemia
#7
Ignacio García-Tuñón, María Hernández-Sánchez, José Luis Ordoñez, Veronica Alonso-Pérez, Miguel Álamo-Quijada, Rocio Benito, Carmen Guerrero, Jesús María Hernández-Rivas, Manuel Sánchez-Martín
CRISPR/Cas9 technology was used to abrogate p210 oncoprotein expression in the Boff-p210 cell line, a pro-B line derived from interlukin-3-dependent Baf/3, that shows IL-3-independence arising from the constitutive expression of BCR-ABL p210. Using this approach, pools of Boff-p210-edited cells and single edited cell-derived clones were obtained and functionally studied in vitro. The loss of p210 expression in Boff-p210 cells resulted in the loss of ability to grow in the absence of IL-3, as the Baf/3 parental line, showing significantly increased apoptosis levels...
February 9, 2017: Oncotarget
https://www.readbyqxmd.com/read/28205241/septic-transfusion-case-caused-by-a-platelet-pool-with-visible-clotting-due-to-contamination-with-staphylococcus-aureus
#8
Maria Loza-Correa, Yuntong Kou, Mariam Taha, Miloslav Kalab, Jennifer Ronholm, Patrick M Schlievert, Michael P Cahill, Robert Skeate, Christine Cserti-Gazdewich, Sandra Ramirez-Arcos
BACKGROUND: Contamination of platelet concentrates (PCs) with Staphylococcus aureus is one of the most significant ongoing transfusion safety risks in developed countries. CASE REPORT: This report describes a transfusion reaction in an elderly patient diagnosed with acute myeloid leukemia, transfused with a 4-day-old buffy coat PC through a central venous catheter. The transfusion was interrupted when a large fibrous clot in the PC obstructed infusion pump flow...
February 16, 2017: Transfusion
https://www.readbyqxmd.com/read/28203711/genome-wide-characterization-of-lncrnas-in-acute-myeloid-leukemia
#9
Lijun Lei, Siyu Xia, Dan Liu, Xiaoqing Li, Jing Feng, Yaqi Zhu, Jun Hu, Linjian Xia, Lieping Guo, Fei Chen, Hui Cheng, Ke Chen, Hanyang Hu, Xiaohua Chen, Feng Li, Shan Zhong, Nupur Mittal, Guohua Yang, Zhijian Qian, Leng Han, Chunjiang He
No abstract text is available yet for this article.
February 15, 2017: Briefings in Bioinformatics
https://www.readbyqxmd.com/read/28202522/histone-acetyltransferase-activity-of-mof-is-required-for-mll-af9-leukemogenesis
#10
Daria G Valerio, Haiming Xu, Chun-Wei Chen, Takayuki Hoshii, Meghan E Eisold, Christopher Delaney, Monica Cusan, Aniruddha J Deshpande, Chun-Hao Huang, Amaia Lujambio, Y George G Zheng, Johannes Zuber, Tej K Pandita, Scott W Lowe, Scott A Armstrong
Chromatin-based mechanisms offer therapeutic targets in acute myeloid leukemia (AML) that are of great current interest. In this study, we conducted an RNAi-based screen to identify druggable chromatin regulator-based targets in leukemias marked by oncogenic rearrangements of the MLL gene. In this manner, we discovered the H4K16 histone acetyltransferase (HAT) MOF to be a potent suppressor of leukemia cell growth. Conditional deletion of Mof in a mouse model of MLL-AF9-driven leukemogenesis reduced tumor burden and prolonged host survival...
February 15, 2017: Cancer Research
https://www.readbyqxmd.com/read/28202519/correlates-of-prenatal-and-early-life-tobacco-smoke-exposure-and-frequency-of-common-gene-deletions-in-childhood-acute-lymphoblastic-leukemia
#11
Adam J de Smith, Maneet Kaur, Semira Gonseth, Alyson A Endicott, Steve Selvin, Luoping Zhang, Ritu Roy, Xiaorong Shao, Helen M Hansen, Alice Y Kang, Kyle M Walsh, Gary V Dahl, Roberta McKean-Cowdin, Catherine Metayer, Joseph L Wiemels
Tobacco smoke exposure has been associated with risk of childhood acute lymphoblastic leukemia (ALL). Understanding the relationship between tobacco exposures and specific mutations may yield etiologic insights. We carried out a case-only analysis to explore whether prenatal and early-life tobacco smoke exposure influences the formation of leukemogenic genomic deletions. Somatic copy-number of 8 genes frequently deleted in ALL (CDKN2A, ETV6, IKZF1, PAX5, RB1, BTG1, PAR1 region, and EBF1) was assessed in 559 pre-treatment tumor samples from the California Childhood Leukemia Study...
February 15, 2017: Cancer Research
https://www.readbyqxmd.com/read/28199841/lineage-specific-genes-are-prominent-dna-damage-hotspots-during-leukemic-transformation-of-b-cell-precursors
#12
Bryant Boulianne, Mark E Robinson, Philippa C May, Leandro Castellano, Kevin Blighe, Jennifer Thomas, Alistair Reid, Markus Müschen, Jane F Apperley, Justin Stebbing, Niklas Feldhahn
In human leukemia, lineage-specific genes represent predominant targets of deletion, with lymphoid-specific genes frequently affected in lymphoid leukemia and myeloid-specific genes in myeloid leukemia. To investigate the basis of lineage-specific alterations, we analyzed global DNA damage in primary B cell precursors expressing leukemia-inducing oncogenes by ChIP-seq. We identified more than 1,000 sensitive regions, of which B lineage-specific genes constitute the most prominent targets. Identified hotspots at B lineage genes relate to DNA-DSBs, affect genes that harbor genomic lesions in human leukemia, and associate with ectopic deletion in successfully transformed cells...
February 14, 2017: Cell Reports
https://www.readbyqxmd.com/read/28197208/molecular-mutations-and-their-cooccurrences-in-cytogenetically-normal-acute-myeloid-leukemia
#13
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/28196983/genomic-profiling-of-acute-lymphoblastic-leukemia-in-ataxia-telangiectasia-patients-reveals-tight-link-between-atm-mutations-and-chromothripsis
#14
M Ratnaparkhe, M Hlevnjak, T Kolb, A Jauch, K K Maass, F Devens, A Rode, V Hovestadt, A Korshunov, A Pastorczak, W Mlynarski, S Sungalee, J Korbel, J Hoell, U Fischer, T Milde, C Kramm, M Nathrath, K Chrzanowska, E Tausch, M Takagi, T Taga, S Constantini, J Loeffen, J Meijerink, S Zielen, G Gohring, B Schlegelberger, E Maass, R Siebert, J Kunz, A E Kulozik, B Worst, D T Jones, S M Pfister, M Zapatka, P Lichter, A Ernst
Recent developments in sequencing technologies led to the discovery of a novel form of genomic instability, termed chromothripsis. This catastrophic genomic event, involved in tumorigenesis, is characterized by tens to hundreds of simultaneously acquired locally clustered rearrangements on one chromosome. We hypothesized that leukemias developing in individuals with Ataxia Telangiectasia, who are born with two mutated copies of the ATM gene, an essential guardian of genome stability, would show a higher prevalence of chromothripsis due to the associated defect in DNA double-strand break repair...
February 15, 2017: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
https://www.readbyqxmd.com/read/28196625/-did-he-who-made-the-lamb-make-thee-new-developments-in-treating-the-fearful-symmetry-of-acute-myeloid-leukemia
#15
REVIEW
Gabriela Brumatti, Najoua Lalaoui, Andrew H Wei, John Silke
Malignant cells must circumvent endogenous cell death pathways to survive and develop into cancers. Acquired cell death resistance also sets up malignant cells to survive anticancer therapies. Acute Myeloid Leukemia (AML) is an aggressive blood cancer characterized by high relapse rate and resistance to cytotoxic therapies. Recent collaborative profiling projects have led to a greater understanding of the 'fearful symmetry' of the genomic landscape of AML, and point to the development of novel potential therapies that can overcome factors linked to chemoresistance...
February 11, 2017: Trends in Molecular Medicine
https://www.readbyqxmd.com/read/28196408/somatic-mutations-in-murine-models-of-leukemia-and-lymphoma-disease-specificity-and-clinical-relevance
#16
Liat Goldberg, Sheryl M Gough, Fan Lee, Christine Dang, Robert L Walker, Yeulin J Zhu, Sven Bilke, Marbin Pineda, Masahiro Onozawa, Yang Jo Chung, Paul S Meltzer, Peter D Aplan
Malignant transformation is a multistep process that is dictated by acquisition of multiple genomic aberrations that provide growth and survival advantage. During the post genomic era, high throughput genomic sequencing has advanced exponentially, leading to identification of countless cancer associated mutations with potential for targeted therapy. Mouse models of cancer serve as excellent tools to examine the functionality of gene mutations and their contribution to the malignant process. However, it remains unclear whether the genetic events that occur during transformation are similar in mice and humans...
February 14, 2017: Genes, Chromosomes & Cancer
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
#17
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/28193567/genomic-analysis-of-adult-b-all-identifies-potential-markers-of-shorter-survival
#18
Shiven Patel, Clinton C Mason, Martha J Glenn, Christian N Paxton, Sara T South, Melissa H Cessna, Julie Asch, Erin F Cobain, Dale L Bixby, Lauren B Smith, Shalini Reshmi, Julie M Gastier-Foster, Joshua D Schiffman, Rodney R Miles
B lymphoblastic leukemia (B-ALL) in adults has a higher risk of relapse and lower long-term survival than pediatric B-ALL, but data regarding genetic prognostic biomarkers are much more limited for adult patients. We identified 70 adult B-ALL patients from three institutions and performed genome-wide analysis via single nucleotide polymorphism (SNP) arrays on DNA isolated from their initial diagnostic sample and, when available, relapse bone marrow specimens to identify recurring copy number alterations (CNA)...
February 3, 2017: Leukemia Research
https://www.readbyqxmd.com/read/28192408/macrophages-confer-survival-signals-via-ccr1-dependent-translational-mcl-1-induction-in-chronic-lymphocytic-leukemia
#19
M H A van Attekum, S Terpstra, E Slinger, M von Lindern, P D Moerland, A Jongejan, A P Kater, E Eldering
Protective interactions with bystander cells in micro-environmental niches, such as lymph nodes (LNs), contribute to survival and therapy resistance of chronic lymphocytic leukemia (CLL) cells. This is caused by a shift in expression of B-cell lymphoma 2 (BCL-2) family members. Pro-survival proteins B-cell lymphoma-extra large (BCL-XL), BCL-2-related protein A1 (BFL-1) and myeloid leukemia cell differentiation protein 1 (MCL-1) are upregulated by LN-residing T cells through CD40L interaction, presumably via nuclear factor (NF)-κB signaling...
February 13, 2017: Oncogene
https://www.readbyqxmd.com/read/28188343/mll5-kmt2e-structure-function-and-clinical-relevance
#20
REVIEW
Xiaoming Zhang, Wisna Novera, Yan Zhang, Lih-Wen Deng
The mixed lineage leukemia (MLL) family of genes, also known as the lysine N-methyltransferase 2 (KMT2) family, are homologous to the evolutionarily conserved trithorax group that plays critical roles in the regulation of homeotic gene (HOX) expression and embryonic development. MLL5, assigned as KMT2E on the basis of its SET domain homology, was initially categorized under MLL (KMT2) family together with other six SET methyltransferase domain proteins (KMT2A-2D and 2F-2G). However, emerging evidence suggests that MLL5 is distinct from the other MLL (KMT2) family members, and the protein it encodes appears to lack intrinsic histone methyltransferase (HMT) activity towards histone substrates...
February 10, 2017: Cellular and Molecular Life Sciences: CMLS
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