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Jesus Duque-Afonso, Chiou-Hong Lin, Kyuho Han, Michael C Wei, Jue Feng, Jason Kurzer, Corina Schneidawind, Stephen H K Wong, Michael C Bassik, Michael L Cleary
There is limited understanding of how signaling pathways are altered by oncogenic fusion transcription factors that drive leukemogenesis. To address this, we interrogated activated signaling pathways in a comparative analysis of mouse and human leukemias expressing the fusion protein E2A-PBX1, which is present in 5-7% of pediatric and 50% of pre-B-cell receptor (preBCR+) acute lymphocytic leukemia (ALL). In this study, we describe remodeling of signaling networks by E2A-PBX1 in pre-B-ALL which result in hyperactivation of the key oncogenic effector enzyme PLCγ2...
October 7, 2016: Cancer Research
Elizabeth J Brisbois, Terry C Major, Marcus J Goudie, Mark E Meyerhoff, Robert H Bartlett, Hitesh Handa
UNLABELLED: Two major problems with implanted catheters are clotting and infection. Nitric oxide (NO) is an endogenous vasodilator as well as natural inhibitor of platelet adhesion/activation and an antimicrobial agent, and NO-releasing polymers are expected to have similar properties. Here, NO-releasing central venous catheters (CVCs) are fabricated using Elast-eon™ E2As polymer with both diazeniumdiolated dibutylhexanediamine (DBHD/NONO) and poly(lactic-co-glycolic acid) (PLGA) additives, where the NO release can be modulated and optimized via the hydrolysis rate of the PLGA...
October 15, 2016: Acta Biomaterialia
Ran He, Shiyue Hou, Cheng Liu, Anli Zhang, Qiang Bai, Miao Han, Yu Yang, Gang Wei, Ting Shen, Xinxin Yang, Lifan Xu, Xiangyu Chen, Yaxing Hao, Pengcheng Wang, Chuhong Zhu, Juanjuan Ou, Houjie Liang, Ting Ni, Xiaoyan Zhang, Xinyuan Zhou, Kai Deng, Yaokai Chen, Yadong Luo, Jianqing Xu, Hai Qi, Yuzhang Wu, Lilin Ye
During chronic viral infection, virus-specific CD8(+) T cells become exhausted, exhibit poor effector function and lose memory potential. However, exhausted CD8(+) T cells can still contain viral replication in chronic infections, although the mechanism of this containment is largely unknown. Here we show that a subset of exhausted CD8(+) T cells expressing the chemokine receptor CXCR5 has a critical role in the control of viral replication in mice that were chronically infected with lymphocytic choriomeningitis virus (LCMV)...
August 2, 2016: Nature
Marcus J Goudie, Elizabeth J Brisbois, Jitendra Pant, Alex Thompson, Joseph A Potkay, Hitesh Handa
Due to the role of nitric oxide (NO) in regulating a variety of biological functions in humans, numerous studies on different NO releasing/generating materials have been published over the past two decades. Although NO has been demonstrated to be a strong antimicrobial and potent antithrombotic agent, NO-releasing (NOrel) polymers have not reached the clinical setting. While increasing the concentration of the NO donor in the polymer is a common method to prolong the NO-release, this should not be at the cost of mechanical strength or biocompatibility of the original material...
2016: International Journal of Polymeric Materials
Yew Ann Leong, Yaping Chen, Hong Sheng Ong, Di Wu, Kevin Man, Claire Deleage, Martina Minnich, Benjamin J Meckiff, Yunbo Wei, Zhaohua Hou, Dimitra Zotos, Kevin A Fenix, Anurag Atnerkar, Simon Preston, Jeffrey G Chipman, Greg J Beilman, Cody C Allison, Lei Sun, Peng Wang, Jiawei Xu, Jesse G Toe, Hao K Lu, Yong Tao, Umaimainthan Palendira, Alexander L Dent, Alan L Landay, Marc Pellegrini, Iain Comerford, Shaun R McColl, Timothy W Schacker, Heather M Long, Jacob D Estes, Meinrad Busslinger, Gabrielle T Belz, Sharon R Lewin, Axel Kallies, Di Yu
During unresolved infections, some viruses escape immunological control and establish a persistant reservoir in certain cell types, such as human immunodeficiency virus (HIV), which persists in follicular helper T cells (TFH cells), and Epstein-Barr virus (EBV), which persists in B cells. Here we identified a specialized group of cytotoxic T cells (TC cells) that expressed the chemokine receptor CXCR5, selectively entered B cell follicles and eradicated infected TFH cells and B cells. The differentiation of these cells, which we have called 'follicular cytotoxic T cells' (TFC cells), required the transcription factors Bcl6, E2A and TCF-1 but was inhibited by the transcriptional regulators Blimp1, Id2 and Id3...
October 2016: Nature Immunology
Jennifer Fraszczak, Anne Helness, Riyan Chen, Charles Vadnais, François Robert, Cyrus Khandanpour, Tarik Möröy
A regulatory circuit that controls myeloid versus B lymphoid cell fate in hematopoietic progenitors has been proposed, in which a network of the transcription factors Egr1/2, Nab, Gfi1 and PU.1 forms the core element. Here we show that a direct link between Gfi1, the transcription factor E2A and its inhibitor Id1 is a critical element of this regulatory circuit. Our data suggest that a certain threshold of Gfi1 is required to gauge E2A activity by adjusting levels of Id1 in multipotent progenitors, which are the first bipotential myeloid/lymphoid-restricted progeny of hematopoietic stem cells...
2016: PloS One
S Eldfors, H Kuusanmäki, M Kontro, M M Majumder, A Parsons, H Edgren, T Pemovska, O Kallioniemi, K Wennerberg, N Gökbuget, T Burmeister, K Porkka, C A Heckman
TCF3-PBX1 (E2A-PBX1) is a recurrent gene fusion in B-cell precursor lymphoblastic leukemia (BCP-ALL), which is caused by the translocation t(1;19)(q23;p13). TCF3-PBX1 BCP-ALL patients typically benefit from chemotherapy; however, many relapse and subsequently develop resistant disease with few effective treatment options. Mechanisms driving disease progression and therapy resistance have not been studied in TCF3-PBX1 BCP-ALL. Here, we aimed to identify novel treatment options for TCF3-PBX1 BCP-ALL by profiling leukemia cells from a relapsed patient, and determine molecular mechanisms underlying disease pathogenesis and progression...
July 27, 2016: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
Alphy Rose-James, R Shiji, P Kusumakumary, Manjusha Nair, Suraj K George, T T Sreelekha
Precise risk stratification and tailored therapy in acute lymphoblastic leukemia (ALL) can lead to enhanced survival rates among children. Translocations and mutations along with multidrug resistance markers are important factors that determine therapeutic efficacy. Gene mutation profiling of patients at the time of diagnosis can offer accurate clinical decision-making. Multiplex PCR was used to screen for various translocations, mutations, and P-glycoprotein (P-gp) status in pediatric ALL samples. The roles of P-gp were analyzed at the transcriptional and translational levels by using real-time PCR and immunoblotting, respectively...
September 2016: Medical Oncology
Badamdorj Bayartogtokh, Ulzhan D Burkitbaeva, Tojoo Enkhbayar
Herein, the description of the adults and immature instars of a newly discovered species, Epidamaeus munkhbayari sp. nov. along with detailed illustrations and data on habitat ecology are provided. Adults of this new species can be easily distinguished form other known species of Epidamaeus by the combination of following characters: two pairs of well-developed prodorsal ridges, the presence of ventral tubercles E2a, Va and Vp, the short, thin interlamellar setae, and the strongly developed tectum of podocephalic fossa...
2016: Zootaxa
Catherine S Schrankel, Cynthia M Solek, Katherine M Buckley, Michele K Anderson, Jonathan P Rast
E-proteins are basic helix-loop-helix (bHLH) transcription factors with essential roles in animal development. In mammals, these are encoded by three loci: E2-2 (ITF-2/ME2/SEF2/TCF4), E2A (TCF3), and HEB (ME1/REB/TCF12). The HEB and E2-2 paralogs are expressed as alternative (Alt) isoforms with distinct N-terminal sequences encoded by unique exons under separate regulatory control. Expression of these alternative transcripts is restricted relative to the longer (Can) forms, suggesting distinct regulatory roles, although the functions of the Alt proteins remain poorly understood...
August 1, 2016: Developmental Biology
Miriam Wöhner, Hiromi Tagoh, Ivan Bilic, Markus Jaritz, Daniela Kostanova Poliakova, Maria Fischer, Meinrad Busslinger
E2A is an essential regulator of early B cell development. Here, we have demonstrated that E2A together with E2-2 controlled germinal center (GC) B cell and plasma cell development. As shown by the identification of regulated E2A,E2-2 target genes in activated B cells, these E-proteins directly activated genes with important functions in GC B cells and plasma cells by inducing and maintaining DNase I hypersensitive sites. Through binding to multiple enhancers in the Igh 3' regulatory region and Aicda locus, E-proteins regulated class switch recombination by inducing both Igh germline transcription and AID expression...
June 27, 2016: Journal of Experimental Medicine
Renee Gloury, Dimitra Zotos, Malou Zuidscherwoude, Frederick Masson, Yang Liao, Jhaguaral Hasbold, Lynn M Corcoran, Phil D Hodgkin, Gabrielle T Belz, Wei Shi, Stephen L Nutt, David M Tarlinton, Axel Kallies
The generation of high-affinity antibodies requires germinal center (GC) development and differentiation of long-lived plasma cells in a multilayered process that is tightly controlled by the activity of multiple transcription factors. Here, we reveal a new layer of complexity by demonstrating that dynamic changes in Id3 and E-protein activity govern both GC and plasma cell differentiation. We show that down-regulation of Id3 in B cells is essential for releasing E2A and E2-2, which in a redundant manner are required for antigen-induced B cell differentiation...
May 30, 2016: Journal of Experimental Medicine
Laura A Shaw, Simon Bélanger, Kyla D Omilusik, Sunglim Cho, James P Scott-Browne, J Philip Nance, John Goulding, Anna Lasorella, Li-Fan Lu, Shane Crotty, Ananda W Goldrath
The differentiation of helper T cells into effector subsets is critical to host protection. Transcription factors of the E-protein and Id families are important arbiters of T cell development, but their role in the differentiation of the TH1 and TFH subsets of helper T cells is not well understood. Here, TH1 cells showed more robust Id2 expression than that of TFH cells, and depletion of Id2 via RNA-mediated interference increased the frequency of TFH cells. Furthermore, TH1 differentiation was blocked by Id2 deficiency, which led to E-protein-dependent accumulation of effector cells with mixed characteristics during viral infection and severely impaired the generation of TH1 cells following infection with Toxoplasma gondii...
July 2016: Nature Immunology
Y-X Hu, J Lu, H-L He, Y Wang, J-Q Li, P-F Xiao, J Li, H Lv, Y-N Sun, J-J Fan, Y-H Chai, S-Y Hu
OBJECTIVE: The aim of this prospective study was to evaluate the cut-off value of minimal residual disease (MRD) in predicting the efficacy of CCLG-ALL-2008 or CCLG-2008 treatment protocol on pediatric B-precursor ALL (BP-ALL). PATIENTS AND METHODS: Three hundred and seventy-nine Chinese pediatric BP-ALL were enrolled in this study between Dec 2008 and Sep 2013 in two stratified cohorts. One hundred and fifty-three patients enrolled between Dec 2008 and Oct 2010 as the first cohort, and 196 patients enrolled from Nov 2010 to Sep 2013 as the second cohort...
May 2016: European Review for Medical and Pharmacological Sciences
Hanfeng Guan, Linka Xie, Thomas Wirth, Alexey Ushmorov
Although Hodgkin and Reed-Sternberg (HRS) cells of classical Hodgkin lymphoma (cHL) derived from germinal or post germinal B cells, they have lost the B cell phenotype in the process of lymphomagenesis. The phenomenon can be at least partially explained by repression of B-cell-specific transcription factors including TCF3, early B-cell factor 1 (EBF1), SPI1/PU.1, and FOXO1, which are down-regulated by genetic and epigenetic mechanisms. The unique phenotype has been suspected to be advantageous for survival of HRS cells...
May 6, 2016: Oncotarget
Xiao-Fei Ai, Yan Zhang, Xin-Rong Shi, Ying-Chun Zheng, Li Zhang, Xiao-Jing Wang, Qing-Hua Li
OBJECTIVE: To explore the application of combined detection of fusion gene and BIOMED-2 standardized immunoglobulin (Ig) gene rearrangement system in diagnosis and treatment of children with acute lymphoblastic leukemia (ALL). METHODS: Multiplex-PCR amplifications and RQ-PCR of RNA/DNA were performed using ALL fusion gene detection kit and BIOMED-2 primer. The Ig gene rearrangements were analyzed by using PCR fragment analysis system. RESULTS: Out of 251 children with B-ALL, 77 cases were TEL-AML1(+) , 28 cases were E2A-PBX1(+) , 10 cases were MLL-AF4(+) , 11 cases were BCR-ABL(+) , the total positive rate was 50...
April 2016: Zhongguo Shi Yan Xue Ye Xue za Zhi
Colin Flinders, Larry Lam, Liudmilla Rubbi, Roberto Ferrari, Sorel Fitz-Gibbon, Pao-Yang Chen, Michael Thompson, Heather Christofk, David B Agus, Daniel Ruderman, Parag Mallick, Matteo Pellegrini
BACKGROUND: The genetic origins of chemotherapy resistance are well established; however, the role of epigenetics in drug resistance is less well understood. To investigate mechanisms of drug resistance, we performed systematic genetic, epigenetic, and transcriptomic analyses of an alkylating agent-sensitive murine lymphoma cell line and a series of resistant lines derived by drug dose escalation. METHODS: Dose escalation of the alkylating agent mafosfamide was used to create a series of increasingly drug-resistant mouse Burkitt's lymphoma cell lines...
2016: Genome Medicine
T Hoang, J A Lambert, R Martin
SCL, a transcription factor of the basic helix-loop-helix family, is a master regulator of hematopoiesis. Scl specifies lateral plate mesoderm to a hematopoietic fate and establishes boundaries by inhibiting the cardiac lineage. A combinatorial interaction between Scl and Vegfa/Flk1 sets in motion the first wave of primitive hematopoiesis. Subsequently, definitive hematopoietic stem cells (HSCs) emerge from the embryo proper via an endothelial-to-hematopoietic transition controlled by Runx1, acting with Scl and Gata2...
2016: Current Topics in Developmental Biology
K J Hewitt, K D Johnson, X Gao, S Keles, E H Bresnick
Transcriptional regulators mediate the genesis and function of the hematopoietic system by binding complex ensembles of cis-regulatory elements to establish genetic networks. While thousands to millions of any given cis-element resides in a genome, how transcriptional regulators select these sites and how site attributes dictate functional output is not well understood. An instructive system to address this problem involves the GATA family of transcription factors that control vital developmental and physiological processes and are linked to multiple human pathologies...
2016: Current Topics in Developmental Biology
Qingshi Zhao, Corey Chang, J Patrick Gonzalez, Kamal Alzahrani, Jessica L Button, Diego Fraidenraich
The Inhibitor of DNA Binding (Id) proteins play a crucial role in regulating hematopoiesis and are known to interact with E proteins and the bHLH family of transcription factors. Current efforts seek to elucidate the individual roles of Id members in regulating hematopoietic development and specification. However, the nature of their functional redundancies remains elusive since ablation of multiple Id genes is embryonically lethal. We developed a model to test this compensation in the adult. We report that global Id3 ablation with Tie2Cre-mediated conditional ablation of Id1 in both hematopoietic and endothelial cells (Id cDKO) extends viability to 1 year but leads to multi-lineage hematopoietic defects including the emergence of anemia associated with defective erythroid development, a novel phenotype unreported in prior single Id knockout studies...
2016: PloS One
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