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RUNX1-ETO

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https://www.readbyqxmd.com/read/29431622/c-ebp%C3%AE-overrides-epigenetic-reprogramming-by-oncogenic-transcription-factors-in-acute-myeloid-leukemia
#1
Justin Loke, Paulynn Suyin Chin, Peter Keane, Anna Pickin, Salam A Assi, Anetta Ptasinska, Maria Rosaria Imperato, Peter N Cockerill, Constanze Bonifer
Acute myeloid leukemia (AML) is a heterogeneous disease caused by recurrent mutations in the transcription regulatory machinery, resulting in abnormal growth and a block in differentiation. One type of recurrent mutations affects RUNX1 , which is subject to mutations and translocations, the latter giving rise to fusion proteins with aberrant transcriptional activities. We recently compared the mechanism by which the products of the t(8;21) and the t(3;21) translocation RUNX1-ETO and RUNX1-EVI1 reprogram the epigenome...
February 13, 2018: Blood Advances
https://www.readbyqxmd.com/read/29105243/performance-of-multiplex-fusion-gene-testing-in-pediatric-acute-myeloid-leukemia
#2
Yuka Iijima-Yamashita, Hidemasa Matsuo, Miho Yamada, Takao Deguchi, Nobutaka Kiyokawa, Akira Shimada, Akio Tawa, Hiroyuki Takahashi, Daisuke Tomizawa, Takashi Taga, Akitoshi Kinoshita, Souichi Adachi, Keizo Horibe
BACKGROUND: Gene abnormalities, particularly chromosome rearrangements generating gene fusions, are associated with clinical characteristics and prognosis in pediatric acute myeloid leukemia (AML). Karyotyping is generally performed to enable risk stratification; however, the results are not always consistent with those generated by reverse transcription-polymerase chain reaction (RT-PCR), and more accurate and rapid methods are required. METHODS: A total of 487 samples from de novo AML patients enrolled in the Japanese Pediatric Leukemia/Lymphoma Study Group (JPLSG) AML-05 study (n = 448), and acute promyelocytic leukemia (APL) patients enrolled in the JPLSG AML-P05 study (n = 39) were available for this investigation...
November 4, 2017: Pediatrics International: Official Journal of the Japan Pediatric Society
https://www.readbyqxmd.com/read/29067751/monitoring-of-fusion-gene-transcripts-to-predict-relapse-in-pediatric-acute-myeloid-leukemia
#3
Hidemasa Matsuo, Yuka Iijima-Yamashita, Miho Yamada, Takao Deguchi, Nobutaka Kiyokawa, Akira Shimada, Akio Tawa, Daisuke Tomizawa, Takashi Taga, Akitoshi Kinoshita, Souichi Adachi, Keizo Horibe
BACKGROUND: In acute myeloid leukemia (AML), accurate detection of minimal residual disease (MRD) enables better risk-stratified therapy. There are few studies, however, on the monitoring of multiple fusion transcripts and evaluation of their accuracy as indicators of MRD at multiple time points. METHODS: We retrospectively examined RNA obtained from 82 pediatric AML patients enrolled in the Japanese Pediatric Leukemia/Lymphoma Study Group (JPLSG) AML-05 study. The expression of six important fusion transcripts (AML1(RUNX1)-ETO, CBFB-MYH11, MLL(KMT2A)-AF9, MLL-ELL, MLL-AF6, and FUS-ERG) was analyzed at five time points 30-40 days apart following diagnosis...
January 2018: Pediatrics International: Official Journal of the Japan Pediatric Society
https://www.readbyqxmd.com/read/29052866/runx-mediated-growth-arrest-and-senescence-are-attenuated-by-diverse-mechanisms-in-cells-expressing-runx1-fusion-oncoproteins
#4
Gail Anderson, Nancy Mackay, Kathryn Gilroy, Jodie Hay, Gillian Borland, Alma McDonald, Margaret Bell, Siti Ayuni Hassanudin, Ewan Cameron, James C Neil, Anna Kilbey
RUNX gene over-expression inhibits growth of primary cells but transforms cells with tumor suppressor defects, consistent with reported associations with tumor progression. In contrast, chromosomal translocations involving RUNX1 are detectable in utero, suggesting an initiating role in leukemias. How do cells expressing RUNX1 fusion oncoproteins evade RUNX-mediated growth suppression? Previous studies showed that the TEL-RUNX1 fusion from t(12;21) B-ALLs is unable to induce senescence-like growth arrest (SLGA) in primary fibroblasts while potent activity is displayed by the RUNX1-ETO fusion found in t(8;21) AMLs...
October 20, 2017: Journal of Cellular Biochemistry
https://www.readbyqxmd.com/read/28915648/synergistic-suppression-of-t-8-21-positive-leukemia-cell-growth-by-combining-oridonin-and-mapk1-erk2-inhibitors
#5
Pavel Spirin, Timofey Lebedev, Natalia Orlova, Alexey Morozov, Nadezhda Poymenova, Sergey E Dmitriev, Anton Buzdin, Carol Stocking, Olga Kovalchuk, Vladimir Prassolov
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...
August 22, 2017: Oncotarget
https://www.readbyqxmd.com/read/28654903/synergistic-suppression-of-t-8-21-positive-leukemia-cell-growth-by-combining-oridonin-and-mapk1-erk2-inhibitors
#6
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
https://www.readbyqxmd.com/read/28538183/runx1-eto-and-runx1-evi1-differentially-reprogram-the-chromatin-landscape-in-t-8-21-and-t-3-21-aml
#7
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
https://www.readbyqxmd.com/read/28299675/a-regulatory-role-for-runx1-runx3-in-the-maintenance-of-genomic-integrity
#8
REVIEW
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
https://www.readbyqxmd.com/read/28299657/runx1-eto-leukemia
#9
REVIEW
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
https://www.readbyqxmd.com/read/28154087/suppression-of-runx1-eto-oncogenic-activity-by-a-small-molecule-inhibitor-of-tetramerization
#10
LETTER
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
https://www.readbyqxmd.com/read/28092997/the-t-8-21-fusion-protein-runx1-eto-downregulates-pkm2-in-acute-myeloid-leukemia-cells
#11
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
https://www.readbyqxmd.com/read/27389055/restoration-of-myc-repressed-targets-mediates-the-negative-effects-of-gm-csf-on-runx1-eto-leukemogenicity
#12
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
https://www.readbyqxmd.com/read/27118388/the-as-rbm15-lncrna-enhances-rbm15-protein-translation-during-megakaryocyte-differentiation
#13
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
https://www.readbyqxmd.com/read/26990877/mir144-451-expression-is-repressed-by-runx1-during-megakaryopoiesis-and-disturbed-by-runx1-eto
#14
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
https://www.readbyqxmd.com/read/26802049/helicase-like-transcription-factor-is-a-runx1-target-whose-downregulation-promotes-genomic-instability-and-correlates-with-complex-cytogenetic-features-in-acute-myeloid-leukemia
#15
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
https://www.readbyqxmd.com/read/26483790/interplay-between-transcription-factors-and-the-epigenome-insight-from-the-role-of-runx1-in-leukemia
#16
REVIEW
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
https://www.readbyqxmd.com/read/26361793/overexpression-and-knockout-of-mir-126-both-promote-leukemogenesis
#17
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
https://www.readbyqxmd.com/read/26333776/wnt-signaling-induces-transcription-spatial-proximity-and-translocation-of-fusion-gene-partners-in-human-hematopoietic-cells
#18
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
https://www.readbyqxmd.com/read/26126967/genome-scale-definition-of-the-transcriptional-programme-associated-with-compromised-pu-1-activity-in-acute-myeloid-leukaemia
#19
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
https://www.readbyqxmd.com/read/26060100/the-leukemia-inhibitory-factor-receptor-gene-is-a-direct-target-of-runx1
#20
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
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