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https://www.readbyqxmd.com/read/29784935/a-causal-mechanism-for-childhood-acute-lymphoblastic-leukaemia
#1
REVIEW
Mel Greaves
In this Review, I present evidence supporting a multifactorial causation of childhood acute lymphoblastic leukaemia (ALL), a major subtype of paediatric cancer. ALL evolves in two discrete steps. First, in utero initiation by fusion gene formation or hyperdiploidy generates a covert, pre-leukaemic clone. Second, in a small fraction of these cases, the postnatal acquisition of secondary genetic changes (primarily V(D)J recombination-activating protein (RAG) and activation-induced cytidine deaminase (AID)-driven copy number alterations in the case of ETS translocation variant 6 (ETV6)-runt-related transcription factor 1 (RUNX1)+ ALL) drives conversion to overt leukaemia...
May 21, 2018: Nature Reviews. Cancer
https://www.readbyqxmd.com/read/29780592/preleukemic-and-second-hit-mutational-events-in-an-acute-myeloid-leukemia-patient-with-a-novel-germline-runx1-mutation
#2
Isaac Ks Ng, Joanne Lee, Christopher Ng, Bustamin Kosmo, Lily Chiu, Elaine Seah, Michelle Meng Huang Mok, Karen Tan, Motomi Osato, Wee-Joo Chng, Benedict Yan, Lip Kun Tan
Background: Germline mutations in the RUNX1 transcription factor give rise to a rare autosomal dominant genetic condition classified under the entity: Familial Platelet Disorders with predisposition to Acute Myeloid Leukaemia (FPD/AML). While several studies have identified a myriad of germline RUNX1 mutations implicated in this disorder, second-hit mutational events are necessary for patients with hereditary thrombocytopenia to develop full-blown AML. The molecular picture behind this process remains unclear...
2018: Biomarker Research
https://www.readbyqxmd.com/read/29778230/etv6-runx1-positive-childhood-acute-lymphoblastic-leukemia-all-the-spectrum-of-clonal-heterogeneity-and-its-impact-on-prognosis
#3
Μ Αmpatzidou, S I Papadhimitriou, G Paterakis, D Pavlidis, Κ Tsitsikas, I V Kostopoulos, V Papadakis, G Vassilopoulos, S Polychronopoulou
The prognostic significance of the ETV6/RUNX1-fusion and of the accompanying aberrations is disputable; whether co-existing sub-clones are responsible for delayed MRD-clearance and thus, moderate outcome, remains to be clarified. We studied, in a paediatric cohort of 119 B-ALLs, the relation between the ETV6/RUNX1 aberration and the co-existing subclones with (a) presenting clinical/biological features, (b) early response to treatment(MRD) and (c) long-term outcome over a 12-year period. Patients were homogeneously treated according to BFM-based-protocols...
August 2018: Cancer Genetics
https://www.readbyqxmd.com/read/29766829/acute-myeloid-leukemia-diagnosis-and-management-based-on-current-molecular-genetics-approach
#4
E Suguna, R Farhana, E Kanimozhi, P SaiKumar, G Kumaramanickavel, Chitralekha Sai Kumar
Background &Objective: Acute myeloid leukemia (AML) is characterized by accumulation of ?20% myeloid premature blast cells in the bone marrow and most often found in the peripheral blood. AML is generally classified based on two groups, namely, French-American-British (FAB) and World Health Organization (WHO) systems. For better clinical management, cytogenetic findings in AML are necessary and in patients with normal karyotypes, molecular analysis becomes critical. Mutations of certain genes like Nucleophosmin 1gene (NPM1), Fms-related Tyrosine Kinase 3 (FLT3), CCAAT/Enhancer Binding Protein Alpha (CEBPA), Runt-related transcription factor 1(RUNX1), and Mixed Lineage Leukemia (MLL) play a crucial role in the risk management and clinical stratification of AML patients...
May 15, 2018: Cardiovascular & Hematological Disorders Drug Targets
https://www.readbyqxmd.com/read/29765516/selective-dissociation-between-lsd1-and-gfi1b-by-a-lsd1-inhibitor-ncd38-induces-the-activation-of-erg-super-enhancer-in-erythroleukemia-cells
#5
Ryusuke Yamamoto, Masahiro Kawahara, Shinji Ito, Junko Satoh, Goichi Tatsumi, Masakatsu Hishizawa, Takayoshi Suzuki, Akira Andoh
Lysine-specific demethylase 1 (LSD1) is a histone modifier for transcriptional repression involved in the regulation of hematopoiesis. We previously reported that a LSD1 inhibitor NCD38 induces transdifferentiation from erythroid lineage to granulomonocytic lineage and exerts anti-leukemia effect through de-repression of the specific super-enhancers of hematopoietic regulators including ERG in a human erythroleukemia cell line, HEL. However, the mechanistic basis for this specificity of NCD38 has remained unclear...
April 20, 2018: Oncotarget
https://www.readbyqxmd.com/read/29764005/identification-of-novel-functional-variants-of-sin3a-and-srsf1-among-somatic-variants-in-acute-myeloid-leukemia-patients
#6
Jae-Woong Min, Youngil Koh, Dae-Yoon Kim, Hyung-Lae Kim, Jeong A Han, Yu-Jin Jung, Sung-Soo Yoon, Sun Shim Choi
The advent of massively parallel sequencing, also called nextgeneration sequencing (NGS), has dramatically influenced cancer genomics by accelerating the identification of novel molecular alterations. Using a whole genome sequencing (WGS) approach, we identified somatic coding and noncoding variants that may contribute to leukemogenesis in 11 adult Korean acute myeloid leukemia (AML) patients, with serial tumor samples (primary and relapse) available for 5 of them; somatic variants were identified in 187 AML-related genes, including both novel (SIN3A, C10orf53, PTPRR, and RERGL) and well-known (NPM1, RUNX1, and CEPBA) AMLrelated genes...
May 15, 2018: Molecules and Cells
https://www.readbyqxmd.com/read/29763473/maternal-folate-genes-and-aberrant-dna-hypermethylation-in-pediatric-acute-lymphoblastic-leukemia
#7
Jeremy M Schraw, Teresa T Yiu, Philip J Lupo, Spiridon Tsavachidis, Rachel Rau, Melissa L Bondy, Karen R Rabin, Lanlan Shen, Michael E Scheurer
BACKGROUND: There is evidence that maternal genotypes in folate-related genes are associated with pediatric acute lymphoblastic leukemia (ALL) independent of offspring genotype. We evaluated the relationship between maternal genotypes in methionine synthase (MTR) and DNA methylation status in ALL to better characterize the molecular mechanism underlying this association. PROCEDURE: We obtained bone marrow samples from 51 patients with ALL at diagnosis and from 6 healthy donors...
2018: PloS One
https://www.readbyqxmd.com/read/29760437/cd82-hypomethylation-is-essential-for-tuberculosis-pathogenesis-via-regulation-of-runx1-rab5-22
#8
Hyun-Jung Koh, Ye-Ram Kim, Jae-Sung Kim, Jin-Seung Yun, Sojin Kim, Sun Young Kim, Kiseok Jang, Chul-Su Yang
The tumor suppressor gene CD82/KAI1 is a member of the tetraspanin superfamily and organizes various membrane-based processes. Mycobacterium tuberculosis (MTB) persists in host macrophages by interfering with phagolysosome biogenesis and inflammatory responses, but the role of CD82 in controlling the intracellular survival of pathogenic mycobacteria within macrophages remains poorly understood. In this study, we demonstrated that the virulent MTB strain H37Rv (MTB Rv) induced CD82 promoter hypomethylation, resulting in CD82 expression...
May 14, 2018: Experimental & Molecular Medicine
https://www.readbyqxmd.com/read/29759484/runt-related-transcription-factor-1-runx1-promotes-tgf-%C3%AE-induced-renal-tubular-epithelial-to-mesenchymal-transition-emt-and-renal-fibrosis-through-the-pi3k-subunit-p110%C3%AE
#9
Tong Zhou, Maocai Luo, Wei Cai, Siyuan Zhou, Danying Feng, Chundi Xu, Hongyan Wang
Renal fibrosis is widely considered a common mechanism leading to end-stage renal failure. Epithelial-to-mesenchymal transition (EMT) plays important roles in the pathogenesis of renal fibrosis. Runt-related transcription factor 1(RUNX1) plays a vital role in hematopoiesis via Endothelial-to-Hematopoietic Transition (EHT), a process that is conceptually similar to EMT, but its role in EMT and renal fibrosis is unclear. Here, we demonstrate that RUNX1 is overexpressed in the processes of TGF-β-induced partial EMT and renal fibrosis and that the expression level of RUNX1 is SMAD3-dependent...
May 11, 2018: EBioMedicine
https://www.readbyqxmd.com/read/29748211/anti-leukemic-efficacy-of-bet-inhibitor-in-a-preclinical-mouse-model-of-mll-af4-infant-all
#10
Michela Bardini, Luca Trentin, Francesca Rizzo, Margherita Vieri, Angela M Savino, Patricia Garrido Castro, Grazia Fazio, Eddy H J Van Roon, Mark Kerstjens, Nicholas N Smithers, Rab K Prinjha, Geertruy Te Kronnie, Giuseppe Basso, Ronald W Stam, Rob Pieters, Andrea Biondi, Giovanni Cazzaniga
MLL-rearranged acute lymphoblastic leukemia occurring in infants is a rare but very aggressive leukemia, typically associated with a dismal prognosis. Despite the development of specific therapeutic protocols, infant patients with MLL-rearranged ALL still suffer from a low cure rate. At present, novel therapeutic approaches are urgently needed. Recently, the use of small molecule inhibitors targeting the epigenetic regulators of the MLL complex emerged as a promising strategy for the development of a targeted therapy...
May 10, 2018: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/29747746/justicia-adhatoda-induces-megakaryocyte-differentiation-through-mitochondrial-ros-generation
#11
Usha Gutti, Jaswant Kumar Komati, Aneesh Kotipalli, Raja Gopal Venakata Saladi, Ravi Kumar Gutti
BACKGROUND: Hepatoprotective activity along with improved survival percentage and hematological parameters prior to whole body irradiation were reported with Justicia adhatoda extracts. PURPOSE: To evaluate the thrombopoietic potential of Justicia adhatoda L. leaf extract in megakaryocyte differentiation METHODS: Ethanol extracts were prepared using soxhlet extraction method, and IC50 value was determined. The effect of ethanol extracts obtained from Justicia adhatoda on megakaryocyte maturation and development in megakaryocytic Dami cell lines was tested...
April 1, 2018: Phytomedicine: International Journal of Phytotherapy and Phytopharmacology
https://www.readbyqxmd.com/read/29747153/molecular-characterization-of-colorectal-signet-ring-cell-carcinoma-using-whole-exome-and-rna-sequencing
#12
Jae-Yong Nam, Bo Young Oh, Hye Kyung Hong, Joon Seol Bae, Tae Won Kim, Sang Yun Ha, Donghyun Park, Woo Yong Lee, Hee Cheol Kim, Seong Hyeon Yun, Yoon Ah Park, Je-Gun Joung, Woong-Yang Park, Yong Beom Cho
BACKGROUND: Signet-ring cell carcinoma (SRCC) is a very rare subtype of colorectal adenocarcinoma (COAD) with a poor clinical prognosis. Although understanding key mechanisms of tumor progression in SRCCs is critical for precise treatment, a comprehensive view of genomic alterations is lacking. MATERIALS AND METHODS: We performed whole-exome sequencing of tumors and matched normal blood as well as RNA sequencing of tumors and matched normal colonic tissues from five patients with SRCC...
May 7, 2018: Translational Oncology
https://www.readbyqxmd.com/read/29739946/notch-signaling-specifies-arterial-type-definitive-hemogenic-endothelium-from-human-pluripotent-stem-cells
#13
Gene I Uenishi, Ho Sun Jung, Akhilesh Kumar, Mi Ae Park, Brandon K Hadland, Ethan McLeod, Matthew Raymond, Oleg Moskvin, Catherine E Zimmerman, Derek J Theisen, Scott Swanson, Owen J Tamplin, Leonard I Zon, James A Thomson, Irwin D Bernstein, Igor I Slukvin
NOTCH signaling is required for the arterial specification and formation of hematopoietic stem cells (HSCs) and lympho-myeloid progenitors in the embryonic aorta-gonad-mesonephros region and extraembryonic vasculature from a distinct lineage of vascular endothelial cells with hemogenic potential. However, the role of NOTCH signaling in hemogenic endothelium (HE) specification from human pluripotent stem cell (hPSC) has not been studied. Here, using a chemically defined hPSC differentiation system combined with the use of DLL1-Fc and DAPT to manipulate NOTCH, we discover that NOTCH activation in hPSC-derived immature HE progenitors leads to formation of CD144+ CD43- CD73- DLL4+ Runx1 + 23-GFP+ arterial-type HE, which requires NOTCH signaling to undergo endothelial-to-hematopoietic transition and produce definitive lympho-myeloid and erythroid cells...
May 8, 2018: Nature Communications
https://www.readbyqxmd.com/read/29733873/runx1-promotes-cell-growth-in-human-t-cell-acute-lymphoblastic-leukemia-by-transcriptional-regulation-of-key-target-genes
#14
Catherine E Jenkins, Samuel Gusscott, Rachel J Wong, Olena O Shevchuk, Gurneet Rana, Vincenzo Giambra, Kateryna Tyshchenko, Rashedul Islam, Martin Hirst, Andrew P Weng
RUNX1 is frequently mutated in T-cell acute lymphoblastic leukemia (T-ALL). The spectrum of RUNX1 mutations has led to the notion that it acts as a tumor suppressor in this context; however, other studies have placed RUNX1 along with transcription factors TAL1 and NOTCH1 as core drivers of an oncogenic transcriptional program. To reconcile these divergent roles, we knocked down RUNX1 in human T-ALL cell lines and deleted Runx1 or Cbfb in primary mouse T-cell leukemias. RUNX1 depletion consistently resulted in reduced cell proliferation and increased apoptosis...
May 4, 2018: Experimental Hematology
https://www.readbyqxmd.com/read/29730354/the-nonreceptor-tyrosine-kinase-c-abl-phosphorylates-runx1-and-regulates-runx1-mediated-megakaryocyte-maturation
#15
Hainan Liu, Yan Cui, Guang-Fei Wang, Qincai Dong, Yebao Yao, Ping Li, Cheng Cao, Xuan Liu
The transcription factor Runx1 is an essential regulator of definitive hematopoiesis, megakaryocyte (MK) maturation, and lymphocyte differentiation. Runx1 mutations that interfere with its transcriptional activity are often present in leukemia patients. Recent work demonstrated that the transcriptional activity of Runx1 is regulated by kinase-mediated phosphorylation. In this study, we showed that c-Abl, but not Arg tyrosine kinase, associated with Runx1 both in cultured cells and in vitro. c-Abl-mediated tyrosine phosphorylation in the Runx1 transcription inhibition domain negatively regulated the transcriptional activity of Runx1 and inhibited Runx1-mediated MK maturation...
May 4, 2018: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/29728305/prognostic-role-of-gene-mutations-in-chronic-myelomonocytic-leukemia-patients-treated-with-hypomethylating-agents
#16
Matthieu Duchmann, Fevzi F Yalniz, Alessandro Sanna, David Sallman, Catherine C Coombs, Aline Renneville, Olivier Kosmider, Thorsten Braun, Uwe Platzbecker, Lise Willems, Lionel Adès, Michaela Fontenay, Raajit Rampal, Eric Padron, Nathalie Droin, Claude Preudhomme, Valeria Santini, Mrinal M Patnaik, Pierre Fenaux, Eric Solary, Raphael Itzykson
Somatic mutations contribute to the heterogeneous prognosis of chronic myelomonocytic leukemia (CMML). Hypomethylating agents (HMAs) are active in CMML, but analyses of small series failed to identify mutations predicting response or survival. We analyzed a retrospective multi-center cohort of 174 CMML patients treated with a median of 7 cycles of azacitidine (n = 68) or decitabine (n = 106). Sequencing data before treatment initiation were available for all patients, from Sanger (n = 68) or next generation (n = 106) sequencing...
April 25, 2018: EBioMedicine
https://www.readbyqxmd.com/read/29725413/expression-levels-of-the-runt-related-transcription-factor-1-and-3-genes-in-the-development-of-acute-myeloid-leukemia
#17
Adrian Krygier, Dagmara Szmajda, Marta Żebrowska, Agnieszka Jeleń, Ewa Balcerczak
The aim of the present study was to evaluate the mRNA expression level of the runt-related transcription factor 1 ( RUNX1 ) and runt-related transcription factor 3 ( RUNX3 ) genes in patients with acute myeloid leukemia (AML). The etiology of AML is not yet fully known, but certain genetic factors may contribute to its manifestation. The RUNX1 and RUNX3 genes have been demonstrated to serve a role in the transcription process. The group investigated in the present study included 43 patients diagnosed with AML, and the relative RUNX1 and RUNX3 expression levels were determined using reverse transcription-quantitative polymerase chain reaction...
May 2018: Oncology Letters
https://www.readbyqxmd.com/read/29721072/glucocorticoids-inhibit-oncogenic-runx1-eto-in-acute-myeloid-leukemia-with-chromosome-translocation-t-8-21
#18
Lianghao Lu, Yefei Wen, Yuan Yao, Fengju Chen, Guohui Wang, Fangrui Wu, Jingyu Wu, Padmini Narayanan, Michele Redell, Qianxing Mo, Yongcheng Song
Acute myeloid leukemia (AML) is a major blood cancer with poor prognosis. New therapies are needed to target oncogene-driven leukemia stem cells, which account for relapse and resistance. Chromosome translocation t(8;21), which produces RUNX1-ETO (R-E) fusion oncoprotein, is found in ~13% AML. R-E dominance negatively inhibits global gene expression regulated by RUNX1, a master transcription factor for hematopoiesis, causing increased self-renewal and blocked cell differentiation of hematopoietic progenitor cells, and eventually leukemia initiation...
2018: Theranostics
https://www.readbyqxmd.com/read/29713515/the-role-of-tal1-in-hematopoiesis-and-leukemogenesis
#19
E R Vagapova, P V Spirin, T D Lebedev, V S Prassolov
TAL1 (SCL/TAL1, T-cell acute leukemia protein 1) is a transcription factor that is involved in the process of hematopoiesis and leukemogenesis. It participates in blood cell formation, forms mesoderm in early embryogenesis, and regulates hematopoiesis in adult organisms. TAL1 is essential in maintaining the multipotency of hematopoietic stem cells (HSC) and keeping them in quiescence (stage G0). TAL1 forms complexes with various transcription factors, regulating hematopoiesis (E2A/HEB, GATA1-3, LMO1-2, Ldb1, ETO2 , RUNX1, ERG, FLI1)...
January 2018: Acta Naturae
https://www.readbyqxmd.com/read/29707107/selective-inhibition-of-bcl-2-is-a-promising-target-in-patients-with-high-risk-myelodysplastic-syndromes-and-adverse-mutational-profile
#20
Veronika Reidel, Johanna Kauschinger, Richard T Hauch, Catharina Müller-Thomas, Niroshan Nadarajah, Rainer Burgkart, Burkhard Schmidt, Dirk Hempel, Anne Jacob, Julia Slotta-Huspenina, Ulrike Höckendorf, Christian Peschel, Wolfgang Kern, Torsten Haferlach, Katharina S Götze, Stefanie Jilg, Philipp J Jost
Somatic mutations in genes such as ASXL1 , RUNX1 , TP53 or EZH2 adversely affect the outcome of patients with myelodysplastic syndromes (MDS). Since selective BCL-2 inhibition is a promising treatment strategy in hematologic malignancies, we tested the therapeutic impact of ABT-199 on MDS patient samples bearing an adverse mutational profile. By gene expression, we found that the level of pro-apoptotic BIM significantly decreased during MDS disease progression in line with an acquired resistance to cell death...
April 3, 2018: Oncotarget
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