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timothy j ley

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https://www.readbyqxmd.com/read/28215704/cpg-island-hypermethylation-mediated-by-dnmt3a-is-a-consequence-of-aml-progression
#1
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/28067246/mutant-u2af1-expressing-cells-are-sensitive-to-pharmacological-modulation-of-the-spliceosome
#2
Cara Lunn Shirai, Brian S White, Manorama Tripathi, Roberto Tapia, James N Ley, Matthew Ndonwi, Sanghyun Kim, Jin Shao, Alexa Carver, Borja Saez, Robert S Fulton, Catrina Fronick, Michelle O'Laughlin, Chandraiah Lagisetti, Thomas R Webb, Timothy A Graubert, Matthew J Walter
Somatic mutations in spliceosome genes are detectable in ∼50% of patients with myelodysplastic syndromes (MDS). We hypothesize that cells harbouring spliceosome gene mutations have increased sensitivity to pharmacological perturbation of the spliceosome. We focus on mutant U2AF1 and utilize sudemycin compounds that modulate pre-mRNA splicing. We find that haematopoietic cells expressing mutant U2AF1(S34F), including primary patient cells, have an increased sensitivity to in vitro sudemycin treatment relative to controls...
January 9, 2017: Nature Communications
https://www.readbyqxmd.com/read/27959731/tp53-and-decitabine-in-acute-myeloid-leukemia-and-myelodysplastic-syndromes
#3
John S Welch, Allegra A Petti, Christopher A Miller, Catrina C Fronick, Michelle O'Laughlin, Robert S Fulton, Richard K Wilson, Jack D Baty, Eric J Duncavage, Bevan Tandon, Yi-Shan Lee, Lukas D Wartman, Geoffrey L Uy, Armin Ghobadi, Michael H Tomasson, Iskra Pusic, Rizwan Romee, Todd A Fehniger, Keith E Stockerl-Goldstein, Ravi Vij, Stephen T Oh, Camille N Abboud, Amanda F Cashen, Mark A Schroeder, Meagan A Jacoby, Sharon E Heath, Kierstin Luber, Megan R Janke, Andrew Hantel, Niloufer Khan, Madina J Sukhanova, Randall W Knoebel, Wendy Stock, Timothy A Graubert, Matthew J Walter, Peter Westervelt, Daniel C Link, John F DiPersio, Timothy J Ley
Background The molecular determinants of clinical responses to decitabine therapy in patients with acute myeloid leukemia (AML) or myelodysplastic syndromes (MDS) are unclear. Methods We enrolled 84 adult patients with AML or MDS in a single-institution trial of decitabine to identify somatic mutations and their relationships to clinical responses. Decitabine was administered at a dose of 20 mg per square meter of body-surface area per day for 10 consecutive days in monthly cycles. We performed enhanced exome or gene-panel sequencing in 67 of these patients and serial sequencing at multiple time points to evaluate patterns of mutation clearance in 54 patients...
November 24, 2016: New England Journal of Medicine
https://www.readbyqxmd.com/read/27821060/visualizing-tumor-evolution-with-the-fishplot-package-for-r
#4
Christopher A Miller, Joshua McMichael, Ha X Dang, Christopher A Maher, Li Ding, Timothy J Ley, Elaine R Mardis, Richard K Wilson
BACKGROUND: Massively-parallel sequencing at depth is now enabling tumor heterogeneity and evolution to be characterized in unprecedented detail. Tracking these changes in clonal architecture often provides insight into therapeutic response and resistance. In complex cases involving multiple timepoints, standard visualizations, such as scatterplots, can be difficult to interpret. Current data visualization methods are also typically manual and laborious, and often only approximate subclonal fractions...
November 7, 2016: BMC Genomics
https://www.readbyqxmd.com/read/27743233/alloionema-similis-n-sp-a-genetically-divergent-sibling-species-of-a-appendiculatum-schneider-1859-rhabditida-alloionematidae-from-invasive-slugs-in-california-usa
#5
Oleksandr Holovachov, Sven Boström, Irma Tandingan De Ley, Rory J Mc Donnell, Salomon Alvarado, Timothy D Paine, Paul De Ley
A new species of Alloionema Schneider, 1859, A. similis n. sp., and the known species A. appendiculatum Schneider, 1859 were isolated from cadavers of invasive slugs in California. Both species are described based on morphology, morphometrics and molecular data. Alloionema similis n. sp. is morphologically very similar to A. appendiculatum but can be distinguished by a more posterior position of the excretory pore in the Kleinform females and longer tail in the Kleinform males. Substantial differences between the two species are, however, found in both 18S and 28S rDNA sequences...
November 2016: Systematic Parasitology
https://www.readbyqxmd.com/read/27471846/n-oxides-rescue-ru-v-in-catalytic-griffith-ley-tpap-alcohol-oxidations
#6
Timothy J Zerk, Peter W Moore, Craig M Williams, Paul V Bernhardt
The redox and ligand exchange reactions of oxido-ruthenium complexes are central to the function of the Sharpless and Griffith-Ley one-step alcohol oxidation protocols. However, their mechanisms have not been elucidated. Cyclic voltammetry and UV-vis spectroelectrochemical analysis of [RuO4](-) has provided new insight into the key ruthenium oxidation states involved in catalysis. Furthermore, the oxidation states sensitive to the presence of the N-oxide co-oxidant N-methylmorpholine N-oxide (NMO), and its role in catalysis, have been determined...
August 11, 2016: Chemical Communications: Chem Comm
https://www.readbyqxmd.com/read/27181063/comprehensive-genomic-analysis-reveals-flt3-activation-and-a-therapeutic-strategy-for-a-patient-with-relapsed-adult-b-lymphoblastic-leukemia
#7
Malachi Griffith, Obi L Griffith, Kilannin Krysiak, Zachary L Skidmore, Matthew J Christopher, Jeffery M Klco, Avinash Ramu, Tamara L Lamprecht, Alex H Wagner, Katie M Campbell, Robert Lesurf, Jasreet Hundal, Jin Zhang, Nicholas C Spies, Benjamin J Ainscough, David E Larson, Sharon E Heath, Catrina Fronick, Shelly O'Laughlin, Robert S Fulton, Vincent Magrini, Sean McGrath, Scott M Smith, Christopher A Miller, Christopher A Maher, Jacqueline E Payton, Jason R Walker, James M Eldred, Matthew J Walter, Daniel C Link, Timothy A Graubert, Peter Westervelt, Shashikant Kulkarni, John F DiPersio, Elaine R Mardis, Richard K Wilson, Timothy J Ley
The genomic events responsible for the pathogenesis of relapsed adult B-lymphoblastic leukemia (B-ALL) are not yet clear. We performed integrative analysis of whole-genome, whole-exome, custom capture, whole-transcriptome (RNA-seq), and locus-specific genomic assays across nine time points from a patient with primary de novo B-ALL. Comprehensive genome and transcriptome characterization revealed a dramatic tumor evolution during progression, yielding a tumor with complex clonal architecture at second relapse...
July 2016: Experimental Hematology
https://www.readbyqxmd.com/read/26689913/patterns-and-functional-implications-of-rare-germline-variants-across-12-cancer-types
#8
Charles Lu, Mingchao Xie, Michael C Wendl, Jiayin Wang, Michael D McLellan, Mark D M Leiserson, Kuan-Lin Huang, Matthew A Wyczalkowski, Reyka Jayasinghe, Tapahsama Banerjee, Jie Ning, Piyush Tripathi, Qunyuan Zhang, Beifang Niu, Kai Ye, Heather K Schmidt, Robert S Fulton, Joshua F McMichael, Prag Batra, Cyriac Kandoth, Maheetha Bharadwaj, Daniel C Koboldt, Christopher A Miller, Krishna L Kanchi, James M Eldred, David E Larson, John S Welch, Ming You, Bradley A Ozenberger, Ramaswamy Govindan, Matthew J Walter, Matthew J Ellis, Elaine R Mardis, Timothy A Graubert, John F Dipersio, Timothy J Ley, Richard K Wilson, Paul J Goodfellow, Benjamin J Raphael, Feng Chen, Kimberly J Johnson, Jeffrey D Parvin, Li Ding
Large-scale cancer sequencing data enable discovery of rare germline cancer susceptibility variants. Here we systematically analyse 4,034 cases from The Cancer Genome Atlas cancer cases representing 12 cancer types. We find that the frequency of rare germline truncations in 114 cancer-susceptibility-associated genes varies widely, from 4% (acute myeloid leukaemia (AML)) to 19% (ovarian cancer), with a notably high frequency of 11% in stomach cancer. Burden testing identifies 13 cancer genes with significant enrichment of rare truncations, some associated with specific cancers (for example, RAD51C, PALB2 and MSH6 in AML, stomach and endometrial cancers, respectively)...
2015: Nature Communications
https://www.readbyqxmd.com/read/26645048/optimizing-cancer-genome-sequencing-and-analysis
#9
Malachi Griffith, Christopher A Miller, Obi L Griffith, Kilannin Krysiak, Zachary L Skidmore, Avinash Ramu, Jason R Walker, Ha X Dang, Lee Trani, David E Larson, Ryan T Demeter, Michael C Wendl, Joshua F McMichael, Rachel E Austin, Vincent Magrini, Sean D McGrath, Amy Ly, Shashikant Kulkarni, Matthew G Cordes, Catrina C Fronick, Robert S Fulton, Christopher A Maher, Li Ding, Jeffery M Klco, Elaine R Mardis, Timothy J Ley, Richard K Wilson
Tumors are typically sequenced to depths of 75-100× (exome) or 30-50× (whole genome). We demonstrate that current sequencing paradigms are inadequate for tumors that are impure, aneuploid or clonally heterogeneous. To reassess optimal sequencing strategies, we performed ultra-deep (up to ~312×) whole genome sequencing (WGS) and exome capture (up to ~433×) of a primary acute myeloid leukemia, its subsequent relapse, and a matched normal skin sample. We tested multiple alignment and variant calling algorithms and validated ~200,000 putative SNVs by sequencing them to depths of ~1,000×...
September 23, 2015: Cell Systems
https://www.readbyqxmd.com/read/26631115/rapid-expansion-of-preexisting-nonleukemic-hematopoietic-clones-frequently-follows-induction-therapy-for-de-novo-aml
#10
Terrence N Wong, Christopher A Miller, Jeffery M Klco, Allegra Petti, Ryan Demeter, Nichole M Helton, Tiandao Li, Robert S Fulton, Sharon E Heath, Elaine R Mardis, Peter Westervelt, John F DiPersio, Matthew J Walter, John S Welch, Timothy A Graubert, Richard K Wilson, Timothy J Ley, Daniel C Link
There is interest in using leukemia-gene panels and next-generation sequencing to assess acute myelogenous leukemia (AML) response to induction chemotherapy. Studies have shown that patients with AML in morphologic remission may continue to have clonal hematopoiesis with populations closely related to the founding AML clone and that this confers an increased risk of relapse. However, it remains unknown how induction chemotherapy influences the clonal evolution of a patient's nonleukemic hematopoietic population...
February 18, 2016: Blood
https://www.readbyqxmd.com/read/26595813/pml-rara-requires-dna-methyltransferase-3a-to-initiate-acute-promyelocytic-leukemia
#11
Christopher B Cole, Angela M Verdoni, Shamika Ketkar, Elizabeth R Leight, David A Russler-Germain, Tamara L Lamprecht, Ryan T Demeter, Vincent Magrini, Timothy J Ley
The DNA methyltransferases DNMT3A and DNMT3B are primarily responsible for de novo methylation of specific cytosine residues in CpG dinucleotides during mammalian development. While loss-of-function mutations in DNMT3A are highly recurrent in acute myeloid leukemia (AML), DNMT3A mutations are almost never found in AML patients with translocations that create oncogenic fusion genes such as PML-RARA, RUNX1-RUNX1T1, and MLL-AF9. Here, we explored how DNMT3A is involved in the function of these fusion genes. We used retroviral vectors to express PML-RARA, RUNX1-RUNX1T1, or MLL-AF9 in bone marrow cells derived from WT or DNMT3A-deficient mice...
January 2016: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/26492932/genomic-analysis-of-germ-line-and-somatic-variants-in-familial-myelodysplasia-acute-myeloid-leukemia
#12
MULTICENTER STUDY
Jane E Churpek, Khateriaa Pyrtel, Krishna-Latha Kanchi, Jin Shao, Daniel Koboldt, Christopher A Miller, Dong Shen, Robert Fulton, Michelle O'Laughlin, Catrina Fronick, Iskra Pusic, Geoffrey L Uy, Evan M Braunstein, Mark Levis, Julie Ross, Kevin Elliott, Sharon Heath, Allan Jiang, Peter Westervelt, John F DiPersio, Daniel C Link, Matthew J Walter, John Welch, Richard Wilson, Timothy J Ley, Lucy A Godley, Timothy A Graubert
Familial clustering of myelodysplastic syndromes (MDSs) and acute myeloid leukemia (AML) can be caused by inherited factors. We screened 59 individuals from 17 families with 2 or more biological relatives with MDS/AML for variants in 12 genes with established roles in predisposition to MDS/AML, and identified a pathogenic germ line variant in 5 families (29%). Extending the screen with a panel of 264 genes that are recurrently mutated in de novo AML, we identified rare, nonsynonymous germ line variants in 4 genes, each segregating with MDS/AML in 2 families...
November 26, 2015: Blood
https://www.readbyqxmd.com/read/26305651/association-between-mutation-clearance-after-induction-therapy-and-outcomes-in-acute-myeloid-leukemia
#13
Jeffery M Klco, Christopher A Miller, Malachi Griffith, Allegra Petti, David H Spencer, Shamika Ketkar-Kulkarni, Lukas D Wartman, Matthew Christopher, Tamara L Lamprecht, Nicole M Helton, Eric J Duncavage, Jacqueline E Payton, Jack Baty, Sharon E Heath, Obi L Griffith, Dong Shen, Jasreet Hundal, Gue Su Chang, Robert Fulton, Michelle O'Laughlin, Catrina Fronick, Vincent Magrini, Ryan T Demeter, David E Larson, Shashikant Kulkarni, Bradley A Ozenberger, John S Welch, Matthew J Walter, Timothy A Graubert, Peter Westervelt, Jerald P Radich, Daniel C Link, Elaine R Mardis, John F DiPersio, Richard K Wilson, Timothy J Ley
IMPORTANCE: Tests that predict outcomes for patients with acute myeloid leukemia (AML) are imprecise, especially for those with intermediate risk AML. OBJECTIVES: To determine whether genomic approaches can provide novel prognostic information for adult patients with de novo AML. DESIGN, SETTING, AND PARTICIPANTS: Whole-genome or exome sequencing was performed on samples obtained at disease presentation from 71 patients with AML (mean age, 50...
August 25, 2015: JAMA: the Journal of the American Medical Association
https://www.readbyqxmd.com/read/25997609/a-practical-deca-gram-scale-ring-expansion-of-r-carvone-to-r-3-methyl-6-isopropenyl-cyclohept-3-enone-1
#14
Leandro de C Alves, André L Desiderá, Kleber T de Oliveira, Sean Newton, Steven V Ley, Timothy J Brocksom
A route to enantiopure (R)-(+)-3-methyl-6-isopropenyl-cyclohept-3-enone-1, an intermediate for terpenoids, has been developed and includes a highly chemo- and regioselective Tiffeneau-Demjanov reaction. Starting from readily available (R)-(-)-carvone, this robust sequence is available on a deca-gram scale and uses flow chemistry for the initial epoxidation reaction. The stereochemistry of the addition of two nucleophiles to the carbonyl group of (R)-(-)-carvone has been determined by X-ray diffraction studies and chemical correlation...
July 28, 2015: Organic & Biomolecular Chemistry
https://www.readbyqxmd.com/read/25965570/mutant-u2af1-expression-alters-hematopoiesis-and-pre-mrna-splicing-in-vivo
#15
Cara Lunn Shirai, James N Ley, Brian S White, Sanghyun Kim, Justin Tibbitts, Jin Shao, Matthew Ndonwi, Brian Wadugu, Eric J Duncavage, Theresa Okeyo-Owuor, Tuoen Liu, Malachi Griffith, Sean McGrath, Vincent Magrini, Robert S Fulton, Catrina Fronick, Michelle O'Laughlin, Timothy A Graubert, Matthew J Walter
Heterozygous somatic mutations in the spliceosome gene U2AF1 occur in ∼ 11% of patients with myelodysplastic syndromes (MDS), the most common adult myeloid malignancy. It is unclear how these mutations contribute to disease. We examined in vivo hematopoietic consequences of the most common U2AF1 mutation using a doxycycline-inducible transgenic mouse model. Mice expressing mutant U2AF1(S34F) display altered hematopoiesis and changes in pre-mRNA splicing in hematopoietic progenitor cells by whole transcriptome analysis (RNA-seq)...
May 11, 2015: Cancer Cell
https://www.readbyqxmd.com/read/25925892/whole-exome-sequencing-reveals-the-order-of-genetic-changes-during-malignant-transformation-and-metastasis-in-a-single-patient-with-nf1-plexiform-neurofibroma
#16
Angela C Hirbe, Sonika Dahiya, Christopher A Miller, Tiandao Li, Robert S Fulton, Xiaochun Zhang, Sandra McDonald, Katherine DeSchryver, Eric J Duncavage, Jessica Walrath, Karlyne M Reilly, Haley J Abel, Melike Pekmezci, Arie Perry, Timothy J Ley, David H Gutmann
PURPOSE: Malignant peripheral nerve sheath tumors (MPNST) occur at increased frequency in individuals with neurofibromatosis type 1 (NF1), where they likely arise from benign plexiform neurofibroma precursors. While previous studies have used a variety of discovery approaches to discover genes associated with MPNST pathogenesis, it is currently unclear what molecular events are associated with the evolution of MPNST from plexiform neurofibroma. EXPERIMENTAL DESIGN: Whole-exome sequencing was performed on biopsy materials representing plexiform neurofibroma (n = 3), MPNST, and metastasis from a single individual with NF1 over a 14-year period...
September 15, 2015: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/25799070/genetic-heterogeneity-of-induced-pluripotent-stem-cells-results-from-24-clones-derived-from-a-single-c57bl-6-mouse
#17
Cheng Li, Jeffery M Klco, Nichole M Helton, Daniel R George, Jacqueline L Mudd, Christopher A Miller, Charles Lu, Robert Fulton, Michelle O'Laughlin, Catrina Fronick, Richard K Wilson, Timothy J Ley
Induced pluripotent stem cells (iPSCs) have tremendous potential as a tool for disease modeling, drug testing, and other applications. Since the generation of iPSCs "captures" the genetic history of the individual cell that was reprogrammed, iPSC clones (even those derived from the same individual) would be expected to demonstrate genetic heterogeneity. To assess the degree of genetic heterogeneity, and to determine whether some cells are more genetically "fit" for reprogramming, we performed exome sequencing on 24 mouse iPSC clones derived from skin fibroblasts obtained from two different sites of the same 8-week-old C57BL/6J male mouse...
2015: PloS One
https://www.readbyqxmd.com/read/25487151/role-of-tp53-mutations-in-the-origin-and-evolution-of-therapy-related-acute-myeloid-leukaemia
#18
Terrence N Wong, Giridharan Ramsingh, Andrew L Young, Christopher A Miller, Waseem Touma, John S Welch, Tamara L Lamprecht, Dong Shen, Jasreet Hundal, Robert S Fulton, Sharon Heath, Jack D Baty, Jeffery M Klco, Li Ding, Elaine R Mardis, Peter Westervelt, John F DiPersio, Matthew J Walter, Timothy A Graubert, Timothy J Ley, Todd E Druley, Daniel C Link, Richard K Wilson
Therapy-related acute myeloid leukaemia (t-AML) and therapy-related myelodysplastic syndrome (t-MDS) are well-recognized complications of cytotoxic chemotherapy and/or radiotherapy. There are several features that distinguish t-AML from de novo AML, including a higher incidence of TP53 mutations, abnormalities of chromosomes 5 or 7, complex cytogenetics and a reduced response to chemotherapy. However, it is not clear how prior exposure to cytotoxic therapy influences leukaemogenesis. In particular, the mechanism by which TP53 mutations are selectively enriched in t-AML/t-MDS is unknown...
February 26, 2015: Nature
https://www.readbyqxmd.com/read/25393105/clonal-architectures-and-driver-mutations-in-metastatic-melanomas
#19
Li Ding, Minjung Kim, Krishna L Kanchi, Nathan D Dees, Charles Lu, Malachi Griffith, David Fenstermacher, Hyeran Sung, Christopher A Miller, Brian Goetz, Michael C Wendl, Obi Griffith, Lynn A Cornelius, Gerald P Linette, Joshua F McMichael, Vernon K Sondak, Ryan C Fields, Timothy J Ley, James J Mulé, Richard K Wilson, Jeffrey S Weber
To reveal the clonal architecture of melanoma and associated driver mutations, whole genome sequencing (WGS) and targeted extension sequencing were used to characterize 124 melanoma cases. Significantly mutated gene analysis using 13 WGS cases and 15 additional paired extension cases identified known melanoma genes such as BRAF, NRAS, and CDKN2A, as well as a novel gene EPHA3, previously implicated in other cancer types. Extension studies using tumors from another 96 patients discovered a large number of truncation mutations in tumor suppressors (TP53 and RB1), protein phosphatases (e...
2014: PloS One
https://www.readbyqxmd.com/read/25349173/caspase-9-is-required-for-normal-hematopoietic-development-and-protection-from-alkylator-induced-dna-damage-in-mice
#20
Elise Peterson Lu, Michael McLellan, Li Ding, Robert Fulton, Elaine R Mardis, Richard K Wilson, Christopher A Miller, Peter Westervelt, John F DiPersio, Daniel C Link, Matthew J Walter, Timothy J Ley, Timothy A Graubert
Apoptosis and the DNA damage responses have been implicated in hematopoietic development and differentiation, as well as in the pathogenesis of myelodysplastic syndromes (MDS) and leukemia. However, the importance of late-stage mediators of apoptosis in hematopoiesis and leukemogenesis has not been elucidated. Here, we examine the role of caspase-9 (Casp9), the initiator caspase of the intrinsic apoptotic cascade, in murine fetal and adult hematopoiesis. Casp9 deficiency resulted in decreased erythroid and B-cell progenitor abundance and impaired function of hematopoietic stem cells after transplantation...
December 18, 2014: Blood
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