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https://www.readbyqxmd.com/read/28231254/rapid-generation-of-drug-resistance-alleles-at-endogenous-loci-using-crispr-cas9-indel-mutagenesis
#1
Jonathan J Ipsaro, Chen Shen, Eri Arai, Yali Xu, Justin B Kinney, Leemor Joshua-Tor, Christopher R Vakoc, Junwei Shi
Genetic alterations conferring resistance to the effects of chemical inhibitors are valuable tools for validating on-target effects in cells. Unfortunately, for many therapeutic targets such alleles are not available. To address this issue, we evaluated whether CRISPR-Cas9-mediated insertion/deletion (indel) mutagenesis can produce drug-resistance alleles at endogenous loci. This method takes advantage of the heterogeneous in-frame alleles produced following Cas9-mediated DNA cleavage, which we show can generate rare alleles that confer resistance to the growth-arrest caused by chemical inhibitors...
2017: PloS One
https://www.readbyqxmd.com/read/28229434/preclinical-pharmacokinetics-and-pharmacodynamics-of-pinometostat-epz-5676-a-first-in-class-small-molecule-s-adenosyl-methionine-competitive-inhibitor-of-dot1l
#2
Nigel J Waters
Acute leukemias bearing mixed lineage leukemia (MLL) rearrangements are aggressive diseases characterized by a poor overall prognosis despite multi-agent chemotherapy. Aberrant fusion proteins involving the MLL histone methyltransferase (HMT) lead to recruitment of DOT1L, to a multi-protein complex resulting in aberrant methylation of histone H3 lysine 79 at MLL target genes, and ultimately enhanced expression of critical genes for hematopoietic differentiation, including HOXA9 and MEIS1, and as such defines the established mechanism for leukemogenesis in MLL-rearrangement (MLL-r) leukemias...
February 22, 2017: European Journal of Drug Metabolism and Pharmacokinetics
https://www.readbyqxmd.com/read/28223935/morus-alba-leaf-lectin-mll-sensitizes-mcf-7-cells-to-anoikis-by-inhibiting-fibronectin-mediated-integrin-fak-signaling-through-ras-and-activation-of-p-38-mapk
#3
Jayaram Saranya, Ganesan Shilpa, Kozhiparambil G Raghu, Sulochana Priya
Lectins are a unique class of carbohydrate binding proteins/glycoproteins, and many of them possess anticancer properties. They can induce cell cycle arrest and apoptosis, inhibit protein synthesis, telomerase activity and angiogenesis in cancer cells. In the present study, we have demonstrated the effect of Morus alba leaf lectin (MLL) on anoikis induction in MCF-7 cells. Anoikis induction in cancer cells has a significant role in preventing early stage metastasis. MLL treatment in monolayers of MCF-7 cells caused significant detachment of cells in a time and concentration dependent manner...
2017: Frontiers in Pharmacology
https://www.readbyqxmd.com/read/28219220/-clinical-significance-of-expressions-of-evi1-and-bre-genes-in-47-acute-leukemia-patients-with-mll-rearrangement
#4
Y L Gong, J R Zhang, J Zhang, S X Bai, J N Cen, H J Shen, H Y Chou, S N Chen, J L Pan
Objective: To investigate the overexpression frequencies of BRE and EVI1, the correlation between BRE and EVI1 expressions and their possible clinical implications in 11q23/MLL rearrangement acute leukemia. Methods: Cytogenetic examination of bone marrow cells was performed by short-term culture method. R-banding technique was used for karyotype analysis. 47 patients were detected by interphase fluorescence in situ hybridization (FISH) with dual-color break apart MLL probe. The expressions of EVI1 and BRE genes were detected by real time quantitative reverse transcription polymerase chain reaction (RQ-PCR) ...
January 14, 2017: Zhonghua Xue Ye Xue za Zhi, Zhonghua Xueyexue Zazhi
https://www.readbyqxmd.com/read/28219219/-clinical-features-and-prognosis-in-cd10-pre-b-acute-lymphoblastic-leukemia
#5
X Y Gong, Y Wang, B C Liu, H Wei, C L Zhou, D Lin, K Q Liu, S N Wei, B F Gong, G J Zhang, Y T Liu, X L Zhao, Y Li, R X Gu, S W Qiu, Y C Mi, J X Wang
Objective: To analyze the clinical features and prognosis of acute lymphoblastic leukemia patients with immunophenotype of CD10(-)pre-B (CD10(-) pre B-ALL) . Methods: 6 adult cases with CD10(-) pre B-ALL immunophenotypes were analyzed retrospectively, related literatures were reviewed to clarify these kind of patients' clinical features and prognosis. Results: CD10(-) pre B-ALL occurred in 1.5% of ALL, 1.8% of B-ALL and 11.5% of pre B-ALL respectively. All the 6 patients were male with the median age as 33...
January 14, 2017: Zhonghua Xue Ye Xue za Zhi, Zhonghua Xueyexue Zazhi
https://www.readbyqxmd.com/read/28215965/menin-regulates-inhbb-expression-through-an-akt-ezh2-mediated-h3k27-histone-modification
#6
Samuele Gherardi, Doriane Ripoche, Ivan Mikaelian, Marie Chanal, Romain Teinturier, Delphine Goehrig, Martine Cordier-Bussat, Chang X Zhang, Ana Hennino, Philippe Bertolino
Although Men1 is a well-known tumour suppressor gene, little is known about the functions of Menin, the protein it encodes for. Since few years, numerous publications support a major role of Menin in the control of epigenetics gene regulation. While Menin interaction with MLL complex favours transcriptional activation of target genes through H3K4me3 marks, Menin also represses gene expression via mechanisms involving the Polycomb repressing complex (PRC). Interestingly, Ezh2, the PRC-methyltransferase that catalyses H3K27me3 repressive marks and Menin have been shown to co-occupy a large number of promoters...
February 12, 2017: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/28210006/a-novel-lsd1-inhibitor-ncd38-ameliorates-mds-related-leukemia-with-complex-karyotype-by-attenuating-leukemia-programs-via-activating-super-enhancers
#7
N Sugino, M Kawahara, G Tatsumi, A Kanai, H Matsui, R Yamamoto, Y Nagai, S Fujii, Y Shimazu, M Hishizawa, T Inaba, A Andoh, T Suzuki, A Takaori-Kondo
Lysine-specific demethylase 1 (LSD1) regulates gene expression by affecting histone modifications and is a promising target for acute myeloid leukemia (AML) with specific genetic abnormalities. Novel LSD1 inhibitors, NCD25 and NCD38, inhibited growth of MLL-AF9 leukemia as well as erythroleukemia, megakaryoblastic leukemia and myelodysplastic syndromes (MDS) overt leukemia cells in the concentration range that normal hematopoiesis was spared. NCD25 and NCD38 invoked the myeloid development programs, hindered the MDS and AML oncogenic programs, and commonly upregulated 62 genes in several leukemia cells...
February 17, 2017: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
https://www.readbyqxmd.com/read/28210005/mll-is-essential-for-nup98-hoxa9-induced-leukemia
#8
Y Shima, M Yumoto, T Katsumoto, I Kitabayashi
Rearrangements involving the NUP98 gene resulting in fusions to several partner genes occur in acute myeloid leukemia and myelodysplastic syndromes. This study demonstrates that the second FG repeat domain of the NUP98 moiety of the NUP98-HOXA9 fusion protein is important for its cell immortalization and leukemogenesis activities. We demonstrate that NUP98-HOXA9 interacts with MLL via this FG repeat domain and that, in the absence of MLL, NUP98-HOXA9-induced cell immortalization and leukemogenesis are severely inhibited...
February 17, 2017: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
https://www.readbyqxmd.com/read/28203345/sweet-s-syndrome-associated-with-clonal-hematopoiesis-of-indeterminate-potential-responsive-to-5-azacitidine
#9
REVIEW
George Yaghmour, Eric Wiedower, Bassam Yaghmour, Sara Nunnery, Eric Duncavage, Mike G Martin
Sweet's syndrome (SS) is a rare condition characterized by the abrupt appearance of painful skin lesions due to neutrophilic dermal infiltration. Hematologic neoplasms, particularly acute myeloid leukemia (AML) and myelodysplastic syndromes (MDSs), have been commonly reported in association with SS. Clonal hematopoiesis of indeterminate potential (CHIP) is an emerging entity that is a precursor state to myeloid neoplasms. CHIP has not been previously associated with SS. We report the case of a 71-year-old man who presented with recurrent, painful edematous and erythematous papules and nodules for 18 months despite treatment with corticosteroids...
February 2017: Therapeutic Advances in Hematology
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/28197208/molecular-mutations-and-their-cooccurrences-in-cytogenetically-normal-acute-myeloid-leukemia
#11
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/28188343/mll5-kmt2e-structure-function-and-clinical-relevance
#12
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
https://www.readbyqxmd.com/read/28186757/thieno-3-2-b-pyrrole-5-carboxamides-as-new-reversible-inhibitors-of-histone-lysine-demethylase-kdm1a-lsd1-part-2-structure-based-drug-design-and-structure-activity-relationship
#13
Paola Vianello, Luca Sartori, Federica Amigoni, Anna Cappa, Giovanni Fagá, Raimondo Fattori, Elena Legnaghi, Giuseppe Ciossani, Andrea Mattevi, Giuseppe Meroni, Loris Moretti, Valentina Cecatiello, Sebastiano Pasqualato, Alessia Romussi, Florian Thaler, Paolo Trifiró, Oronza A Botrugno, Manuela Villa, Paola Dessanti, Saverio Minucci, Stefania Vultaggio, Elisa Zagarrí, Mario Varasi, Ciro Mercurio
The balance of methylation levels at histone H3 lysine 4 (H3K4) is regulated by KDM1A (LSD1). KDM1A is overexpressed in several tumor types, thus representing an emerging target for the development of novel cancer therapeutics. We have previously described (Part 1) the identification of thieno[3,2-b]pyrrole-5-carboxamides, as novel reversible inhibitors of KDM1A, whose preliminary exploration resulted in compound 2 with biochemical IC50 = 160 nM. We now report the structure-guided optimization of this chemical series, based on multiple ligand/KDM1A-CoRest co-crystal structures, which led to several extremely potent inhibitors...
February 10, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28185526/low-expression-of-ash2l-protein-correlates-with-a-favorable-outcome-in-acute-myeloid-leukemia
#14
Jill S Butler, Yi Hua Qiu, Nianxiang Zhang, Suk-Young Yoo, Kevin R Coombes, Sharon Y R Dent, Steven M Kornblau
ASH2L encodes a trithorax group protein that is a core component of all characterized mammalian histone H3K4 methyltransferase complexes, including mixed lineage leukemia (MLL) complexes. ASH2L protein levels in primary leukemia patient samples have not yet been defined. We analyzed ASH2L protein expression in 511 primary AML patient samples using reverse phase protein array (RPPA) technology. We discovered that ASH2L expression is significantly increased in a subset of patients carrying fms-related tyrosine kinase 3 (FLT3) mutations...
May 2017: Leukemia & Lymphoma
https://www.readbyqxmd.com/read/28185071/sagittal-spinal-alignment-in-asymptomatic-patients-over-30%C3%A2-years-old-in-the-korean-population
#15
Seil Sohn, Chun Kee Chung, Yongjung Jay Kim, Inbo Han, Su Min Kang, Ji Won Yoon, Hyejin Kim
BACKGROUND: We aim to provide sagittal and pelvic parameters according to different age groups in an asymptomatic population all over 30 years old and to investigate the possible causes of changes in these parameters. METHODS: Whole-spine, standing lateral radiographs were taken in 128 asymptomatic Korean people over 30 years old. The spinal parameters (the total thoracic kyphosis (TTK), maximal lumbar lordosis (MLL), total lumbar lordosis (TLL), lower lumbar lordosis (LLL), thoracolumbar junctional angle (TLJA), and lumbar inclination (LI)), pelvic parameters (pelvic incidence (PI), sacral slope (SS), and pelvic tilt (PT)), and spinal balance parameters (spinal balance, sacropelvic balance, and spinopelvic balance) were measured...
February 9, 2017: Acta Neurochirurgica
https://www.readbyqxmd.com/read/28179274/mouse-models-of-mll-leukemia-recapitulating-the-human-disease
#16
Thomas A Milne
Chromosome translocations involving the Mixed Lineage Leukemia (MLL) gene fuse it in frame with multiple partner genes creating novel fusion proteins (MLL-FPs) that cause aggressive acute leukemias in humans. Animal models of human disease are important for the exploration of underlying disease mechanisms as well for testing novel therapeutic approaches. Patients carrying MLL-FPs have very few cooperating mutations, making MLL-FP driven leukemias ideal for animal modeling. This has allowed for a wide range of different experimental model systems designed to explore different aspects of MLL-FP leukemogenesis...
February 8, 2017: Blood
https://www.readbyqxmd.com/read/28168755/palbociclib-can-overcome-mutations-in-cyclin-dependent-kinase-6-that-break-hydrogen-bonds-between-the-drug-and-the-protein
#17
Stella Hernandez Maganhi, Patrizia Jensen, Ignez Caracelli, Julio Zukerman Schpector, Stefan Fröhling, Ran Friedman
Inhibition of cyclin dependent kinases (CDKs) 4 and 6 prevent cells from entering the synthesis phase of the cell cycle. CDK4 and 6 are therefore important drug targets in various cancers. The selective CDK4/6 inhibitor palbociclib is approved for the treatment of breast cancer and has shown activity in a cellular model of mixed lineage leukaemia (MLL)-rearranged acute myeloid leukaemia (AML). We studied the interactions of palbociclib and CDK6 using molecular dynamics simulations. Analysis of the simulations suggested several interactions that stabilised the drug in its binding site and that were not observed in the crystal structure of the protein-drug complex...
February 7, 2017: Protein Science: a Publication of the Protein Society
https://www.readbyqxmd.com/read/28166755/testing-the-potential-significance-of-different-scion-rootstock-genotype-combinations-on-the-ecology-of-old-cultivated-olive-trees-in-the-southeast-mediterranean-area
#18
Oz Barazani, Yoni Waitz, Yizhar Tugendhaft, Michael Dorman, Arnon Dag, Mohammed Hamidat, Thameen Hijawi, Zohar Kerem, Erik Westberg, Joachim W Kadereit
BACKGROUND: A previous multi-locus lineage (MLL) analysis of SSR-microsatellite data of old olive trees in the southeast Mediterranean area had shown the predominance of the Souri cultivar (MLL1) among grafted trees. The MLL analysis had also identified an MLL (MLL7) that was more common among rootstocks than other MLLs. We here present a comparison of the MLL combinations MLL1 (scion)/MLL7 (rootstock) and MLL1/MLL1 in order to investigate the possible influence of rootstock on scion phenotype...
February 6, 2017: BMC Ecology
https://www.readbyqxmd.com/read/28165739/discovery-of-novel-disruptor-of-silencing-telomeric-1-like-dot1l-inhibitors-using-a-target-specific-scoring-function-for-the-s-adenosyl-l-methionine-sam-dependent-methyltransferase-family
#19
Yulan Wang, Linjuan Li, Bidong Zhang, Jing Xing, Shijie Chen, Wei Wan, Yakai Song, Hao Jiang, Hualiang Jiang, Cheng Luo, Mingyue Zheng
The disruptor of telomeric silencing 1-like (DOT1L) protein is a histone H3K79 methyltransferase that plays a key role in transcriptional elongation and cell cycle regulation and is required for the development and maintenance of MLL-rearranged mixed lineage leukemia. Much effort has been dedicated toward discovering novel scaffold DOT1L inhibitors using different strategies. Here, we report the development and application of a target-specific scoring function, the SAM score, for (S)-adenosyl-l-methionine (SAM)-dependent methyltransferases, for the discovery of novel DOT1L inhibitors...
February 21, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28160335/targeting-human-set1-mll-family-of-proteins
#20
REVIEW
Masoud Vedadi, Levi Blazer, Mohammad S Eram, Dalia Barsyte-Lovejoy, Cheryl H Arrowsmith, Taraneh Hajian
The SET1 family of proteins, and in particular MLL1, are essential regulators of transcription and key mediators of normal development and disease. Here, we summarize the detailed characterization of the methyltransferase activity of SET1 complexes and the role of the key subunits, WDR5, RbBP5, ASH2L and DPY30. We present new data on full kinetic characterization of human MLL1, MLL3, SET1A and SET1B trimeric, tetrameric and pentameric complexes to elaborate on substrate specificities and compare our findings with what has been reported before...
February 4, 2017: Protein Science: a Publication of the Protein Society
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