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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...
July 8, 2016: 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...
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...
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
S Rodriguez-Perales, R Torres-Ruiz, J Suela, F Acquadro, M C Martin, E Yebra, J C Ramirez, S Alvarez, J C Cigudosa
We have identified a new t(1;21)(p32;q22) chromosomal translocation in a MDS/AML patient that results in expression of an aberrant C-terminally truncated RUNX1 protein lacking several regulatory domains. As similar truncated RUNX1 proteins are generated by genetic aberrations including chromosomal translocations and point mutations, we used the t(1;21)(p32;q22) chromosomal translocation as a model to explore whether C-terminally truncated RUNX1 proteins trigger effects similar to those induced by well-characterized leukemogenic RUNX1 fusion genes...
January 7, 2016: Oncogene
Arun Kumar Arumugam Raajasekar, Anuradha Belur, Abhinav Chandra
SESSION TITLE: Cancer Student/Resident Case Report Posters IIISESSION TYPE: Medical Student/Resident Case ReportPRESENTED ON: Tuesday, October 28, 2014 at 01:30 PM - 02:30 PMINTRODUCTION: Myeloid sarcoma is a localized extramedullary tumor composed of immature myeloid cells. It can occur in a patient with no prior history of acute myeloid leukemia[1]. It is usually seen in association with acute leukemia, myeloproliferative neoplasm, and myelodysplastic syndromes. They have a predilection for the skin, lymph nodes, small intestine, spine, and the mean time between the diagnosis and development of AML 10...
October 1, 2014: Chest
Anetta Ptasinska, Salam A Assi, Natalia Martinez-Soria, Maria Rosaria Imperato, Jason Piper, Pierre Cauchy, Anna Pickin, Sally R James, Maarten Hoogenkamp, Dan Williamson, Mengchu Wu, Daniel G Tenen, Sascha Ott, David R Westhead, Peter N Cockerill, Olaf Heidenreich, Constanze Bonifer
Oncogenic transcription factors such as RUNX1/ETO, which is generated by the chromosomal translocation t(8;21), subvert normal blood cell development by impairing differentiation and driving malignant self-renewal. Here, we use digital footprinting and chromatin immunoprecipitation sequencing (ChIP-seq) to identify the core RUNX1/ETO-responsive transcriptional network of t(8;21) cells. We show that the transcriptional program underlying leukemic propagation is regulated by a dynamic equilibrium between RUNX1/ETO and RUNX1 complexes, which bind to identical DNA sites in a mutually exclusive fashion...
September 25, 2014: Cell Reports
Alexandr A Migas, Olga A Mishkova, Tatiana V Ramanouskaya, Ilya M Ilyushonak, Olga V Aleinikova, Vasily V Grinev
The RUNX1-RUNX1T1 fusion gene, a product of the nonhomologous balanced translocation t(8;21)(q22;q22), is a complex genetic locus. We performed extensive bioinformatic analysis of transcription initiation as well as transcription termination sites in this locus and predicted a number of different RUNX1T1 transcripts. To confirm and quantify the RUNX1T1 gene expression, we analyzed samples from seven acute myeloid leukemia (AML) patients and from the Kasumi-1 cell line. We found variable activity of the four predicted RUNX1T1 promoters located downstream of the chromosome breakpoint...
September 2014: Leukemia Research
C Wichmann, I Quagliano-Lo Coco, Ö Yildiz, L Chen-Wichmann, H Weber, T Syzonenko, C Döring, C Brendel, K Ponnusamy, A Kinner, C Brandts, R Henschler, M Grez
The RUNX1/ETO (RE) fusion protein, which originates from the t(8;21) chromosomal rearrangement, is one of the most frequent translocation products found in de novo acute myeloid leukemia (AML). In RE leukemias, activated forms of the c-KIT tyrosine kinase receptor are frequently found, thereby suggesting oncogenic cooperativity between these oncoproteins in the development and maintenance of t(8;21) malignancies. In this report, we show that activated c-KIT cooperates with a C-terminal truncated variant of RE, REtr, to expand human CD34+ hematopoietic progenitors ex vivo...
February 2015: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
Boris Rebolledo-Jaramillo, Ricardo A Alarcon, Valentina I Fernandez, Soraya E Gutierrez
BACKGROUND: Human RUNX1 gene is one of the most frequent target for chromosomal translocations associated with acute myeloid leukemia (AML) and acute lymphoid leukemia (ALL). The highest prevalence in AML is noted with (8; 21) translocation; which represents 12 to 15% of all AML cases. Interestingly, all the breakpoints mapped to date in t(8;21) are clustered in intron 5 of the RUNX1 gene and intron 1 of the ETO gene. No homologous sequences have been found at the recombination regions; but DNase I hypersensitive sites (DHS) have been mapped to the areas of the genes involved in t(8;21)...
2014: BMC Genomics
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