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Pavel Spirin, Timofey Lebedev, Natalia Orlova, Alexey Morozov, Nadezhda Poymenova, Sergey E Dmitriev, Anton Buzdin, Carol Stocking, Kovalchuk Olga, Prassolov Vladimir
One of the most common chromosomal translocations in acute myeloid leukemia is t(8;21)(q22;q22), which results in the appearance of abnormal transcripts encoding for the fusion protein RUNX1-ETO. Therefore, this oncoprotein is considered to be a pertinent and promising target for treating t(8;21) leukemia. Previously, we have shown that downregulation of RUNX1-ETO leads to activation of intracellular signaling pathways enhancing cell survival and determined that the protein ERK2 can mediate activation of most of these pathways...
June 16, 2017: Oncotarget
Justin Loke, Salam A Assi, Maria Rosaria Imperato, Anetta Ptasinska, Pierre Cauchy, Yura Grabovska, Natalia Martinez Soria, Manoj Raghavan, H Ruud Delwel, Peter N Cockerill, Olaf Heidenreich, Constanze Bonifer
Acute myeloid leukemia (AML) is a heterogeneous disease caused by mutations in transcriptional regulator genes, but how different mutant regulators shape the chromatin landscape is unclear. Here, we compared the transcriptional networks of two types of AML with chromosomal translocations of the RUNX1 locus that fuse the RUNX1 DNA-binding domain to different regulators, the t(8;21) expressing RUNX1-ETO and the t(3;21) expressing RUNX1-EVI1. Despite containing the same DNA-binding domain, the two fusion proteins display distinct binding patterns, show differences in gene expression and chromatin landscape, and are dependent on different transcription factors...
May 23, 2017: Cell Reports
Vaidehi Krishnan, Yoshiaki Ito
All human cells are constantly attacked by endogenous and exogenous agents that damage the integrity of their genomes. Yet, the ensuing damage is mostly fixed and very rarely gives rise to genomic defects that promote cancer formation. This is due to the co-ordinated functioning of DNA repair proteins and checkpoint mechanisms that accurately detect and repair DNA damage to ensure genomic fitness. According to accumulating evidence, the RUNX family of transcription factors participate in the maintenance of genomic stability through transcriptional and non-transcriptional mechanisms...
2017: Advances in Experimental Medicine and Biology
Shan Lin, James C Mulloy, Susumu Goyama
AML1-ETO leukemia is the most common cytogenetic subtype of acute myeloid leukemia, defined by the presence of t(8;21). Remarkable progress has been achieved in understanding the molecular pathogenesis of AML1-ETO leukemia. Proteomic surveies have shown that AML-ETO forms a stable complex with several transcription factors, including E proteins. Genome-wide transcriptome and ChIP-seq analyses have revealed the genes directly regulated by AML1-ETO, such as CEBPA. Several lines of evidence suggest that AML1-ETO suppresses endogenous DNA repair in cells to promote mutagenesis, which facilitates acquisition of cooperating secondary events...
2017: Advances in Experimental Medicine and Biology
Julia Schanda, Chun-Wei Lee, Katharina Wohlan, Uta Müller-Kuller, Hana Kunkel, Isabell Quagliano-Lo Coco, Stefan Stein, Alexander Metz, Joachim Koch, Jörn Lausen, Uwe Platzbecker, Hind Medyouf, Holger Gohlke, Michael Heuser, Matthias Eder, Manuel Grez, Michaela Scherr, Christian Wichmann
No abstract text is available yet for this article.
May 2017: Haematologica
Jin-Song Yan, Yi-Dong Li, Su-Hui Liu, Qian-Qian Yin, Xin-Yi Liu, Li Xia, Ying Lu
No abstract text is available yet for this article.
August 2017: Leukemia & Lymphoma
S Weng, S Matsuura, C T Mowery, S A Stoner, K Lam, D Ran, A G Davis, M-C Lo, D-E Zhang
Granulocyte macrophage-colony-stimulating factor (GM-CSF) signaling regulates hematopoiesis and immune responses. CSF2RA, the gene encoding the α-subunit for GM-CSF, is significantly downregulated in t(8;21) (RUNX1-ETO or RE) leukemia patients, suggesting that it may serve as a tumor suppressor. We previously reported that GM-CSF signaling is inhibitory to RE leukemogenesis. Here we conducted gene expression profiling of primary RE hematopoietic stem/progenitor cells (HSPCs) treated with GM-CSF to elucidate the mechanisms mediating the negative effects of GM on RE leukemogenicity...
January 2017: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
Ngoc-Tung Tran, Hairui Su, Alireza Khodadadi-Jamayran, Shan Lin, Li Zhang, Dewang Zhou, Kevin M Pawlik, Tim M Townes, Yabing Chen, James C Mulloy, Xinyang Zhao
Antisense RNAs regulate the transcription and translation of the corresponding sense genes. Here, we report that an antisense RNA, AS-RBM15, is transcribed in the opposite direction within exon 1 of RBM15 RBM15 is a regulator of megakaryocyte (MK) differentiation and is also involved in a chromosome translocation t(1;22) in acute megakaryocytic leukemia. MK terminal differentiation is enhanced by up-regulation of AS-RBM15 expression and attenuated by AS-RBM15 knockdown. At the molecular level, AS-RBM15 enhances RBM15 protein translation in a CAP-dependent manner...
June 2016: EMBO Reports
Nicole Kohrs, Stephan Kolodziej, Olga N Kuvardina, Julia Herglotz, Jasmin Yillah, Stefanie Herkt, Alexander Piechatzek, Gabriela Salinas Riester, Thomas Lingner, Christian Wichmann, Halvard Bonig, Erhard Seifried, Uwe Platzbecker, Hind Medyouf, Manuel Grez, Jörn Lausen
A network of lineage-specific transcription factors and microRNAs tightly regulates differentiation of hematopoietic stem cells along the distinct lineages. Deregulation of this regulatory network contributes to impaired lineage fidelity and leukemogenesis. We found that the hematopoietic master regulator RUNX1 controls the expression of certain microRNAs, of importance during erythroid/megakaryocytic differentiation. In particular, we show that the erythorid miR144/451 cluster is epigenetically repressed by RUNX1 during megakaryopoiesis...
March 2016: PLoS Genetics
Chi Keung Cheng, Natalie P H Chan, Thomas S K Wan, Lai Ying Lam, Coty H Y Cheung, Terry H Y Wong, Rosalina K L Ip, Raymond S M Wong, Margaret H L Ng
Helicase-like transcription factor is a SWI/SNF chromatin remodeling factor involved in various biological processes. However, little is known about its role in hematopoiesis. In this study, we measured helicase-like transcription factor mRNA expression in the bone marrow of 204 adult patients with de novo acute myeloid leukemia. Patients were dichotomized into low and high expression groups at the median level for clinicopathological correlations. Helicase-like transcription factor levels were dramatically reduced in the low expression patient group compared to those in the normal controls (n=40) (P<0...
April 2016: Haematologica
Kate H Brettingham-Moore, Phillippa C Taberlay, Adele F Holloway
The genome has the ability to respond in a precise and co-ordinated manner to cellular signals. It achieves this through the concerted actions of transcription factors and the chromatin platform, which are targets of the signaling pathways. Our understanding of the molecular mechanisms through which transcription factors and the chromatin landscape each control gene activity has expanded dramatically over recent years, and attention has now turned to understanding the complex, multifaceted interplay between these regulatory layers in normal and disease states...
2015: Frontiers in Immunology
Zejuan Li, Ping Chen, Rui Su, Yuanyuan Li, Chao Hu, Yungui Wang, Stephen Arnovitz, Miao He, Sandeep Gurbuxani, Zhixiang Zuo, Abdel G Elkahloun, Shenglai Li, Hengyou Weng, Hao Huang, Mary Beth Neilly, Shusheng Wang, Eric N Olson, Richard A Larson, Michelle M Le Beau, Jiwang Zhang, Xi Jiang, Minjie Wei, Jie Jin, Paul P Liu, Jianjun Chen
It is generally assumed that gain- and loss-of-function manipulations of a functionally important gene should lead to the opposite phenotypes. We show in this study that both overexpression and knockout of microRNA (miR)-126 surprisingly result in enhanced leukemogenesis in cooperation with the t(8;21) fusion genes AML1-ETO/RUNX1-RUNX1T1 and AML1-ETO9a (a potent oncogenic isoform of AML1-ETO). In accordance with our observation that increased expression of miR-126 is associated with unfavorable survival in patients with t(8;21) acute myeloid leukemia (AML), we show that miR-126 overexpression exhibits a stronger effect on long-term survival and progression of AML1-ETO9a-mediated leukemia stem cells/leukemia initiating cells (LSCs/LICs) in mice than does miR-126 knockout...
October 22, 2015: Blood
Giorgia D Ugarte, Macarena F Vargas, Matías A Medina, Pablo León, David Necuñir, Alvaro A Elorza, Soraya E Gutiérrez, Randall T Moon, Alejandra Loyola, Giancarlo V De Ferrari
Chromosomal translocations are frequently associated with a wide variety of cancers, particularly hematologic malignancies. A recurrent chromosomal abnormality in acute myeloid leukemia is the reciprocal translocation t(8;21) that fuses RUNX1 and ETO genes. We report here that Wnt/β-catenin signaling increases the expression of ETO and RUNX1 genes in human hematopoietic progenitors. We found that β-catenin is rapidly recruited into RNA polymerase II transcription factories (RNAPII-Ser5) and that ETO and RUNX1 genes are brought into close spatial proximity upon Wnt3a induction...
October 8, 2015: Blood
J I Sive, S Basilico, R Hannah, S J Kinston, F J Calero-Nieto, B Göttgens
Transcriptional dysregulation is associated with haematological malignancy. Although mutations of the key haematopoietic transcription factor PU.1 are rare in human acute myeloid leukaemia (AML), they are common in murine models of radiation-induced AML, and PU.1 downregulation and/or dysfunction has been described in human AML patients carrying the fusion oncogenes RUNX1-ETO and PML-RARA. To study the transcriptional programmes associated with compromised PU.1 activity, we adapted a Pu.1-mutated murine AML cell line with an inducible wild-type PU...
January 2016: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
Abeer A Qadi, Phillippa C Taberlay, Jessica L Phillips, Arabella Young, Alison C West, Kate H Brettingham-Moore, Joanne L Dickinson, Adele F Holloway
Activation of cytokine signaling via the leukemia inhibitory factor receptor (LIFR) plays an integral role in hematopoiesis, osteogenesis, and placental development, along with mediating neurotrophic mechanisms. However, the regulatory control of the LIFR gene has remained largely unexplored. Here, we characterize the LIFR gene as a novel target of the RUNX1 transcription factor. The RUNX1 transcription factor is an essential regulator of hematopoiesis and is a frequent target of point mutations and chromosomal alterations in leukemia...
January 2016: Journal of Cellular Biochemistry
V J Forster, M H Nahari, N Martinez-Soria, A K Bradburn, A Ptasinska, S A Assi, S E Fordham, H McNeil, C Bonifer, O Heidenreich, J M Allan
No abstract text is available yet for this article.
January 2016: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
Kakkad Regha, Salam A Assi, Olga Tsoulaki, Jane Gilmour, Georges Lacaud, Constanze Bonifer
Acute myeloid leukaemia (AML) is characterized by a block in myeloid differentiation the stage of which is dependent on the nature of the transforming oncogene and the developmental stage of the oncogenic hit. This is also true for the t(8;21) translocation that gives rise to the RUNX1-ETO fusion protein and initiates the most common form of human AML. Here we study the differentiation of mouse embryonic stem cells expressing an inducible RUNX1-ETO gene into blood cells as a model, combined with genome-wide analyses of transcription factor binding and gene expression...
May 28, 2015: Nature Communications
Stacy Cooper, Hong Guo, Alan D Friedman
The murine Cebpa gene contains an evolutionarily conserved 453 bp enhancer located at +37 kb that, together with its promoter, directs expression to myeloid progenitors and to long-term hematopoietic stem cells in transgenic mice. In human acute myeloid leukemia cases, the enhancer lacks point mutations but binds the RUNX1-ETO oncoprotein. The enhancer contains the H3K4me1 and H3K27Ac histone modifications, denoting an active enhancer, at progressively increasing levels as long-term hematopoietic stem cells transition to granulocyte-monocyte progenitors...
2015: PloS One
K Ponnusamy, N Kohrs, A Ptasinska, S A Assi, T Herold, W Hiddemann, J Lausen, C Bonifer, R Henschler, C Wichmann
RUNX1/ETO (RE), the t(8;21)-derived leukemic transcription factor associated with acute myeloid leukemia (AML) development, deregulates genes involved in differentiation, self-renewal and proliferation. In addition, these cells show differences in cellular adhesion behavior whose molecular basis is not well understood. Here, we demonstrate that RE epigenetically silences the gene encoding P-Selectin Glycoprotein Ligand-1 (PSGL-1) and downregulates PSGL-1 expression in human CD34+ and murine lin- hematopoietic progenitor cells...
April 13, 2015: Oncogenesis
Sharad Sawney, Rashi Arora, Kamal K Aggarwal, Daman Saluja
One of the most frequent genetic aberrations in acute myeloid leukemia (AML) is chromosomal translocation between AML1/RUNX1 on chromosome 21 and ETO gene on chromosome 8 resulting in the expression of chimeric oncogene AML1-ETO. Although patients with t(8;21) translocation have good prognosis, 5-year survival is observed only in 50% of the cases. AML1-ETO translocation is usually accompanied by overexpression of mutant C-Kit, a tyrosine kinase, which contributes to uncontrolled proliferation of premature blood cells leading to relapse and poor prognosis...
2015: Journal of Oncology
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