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https://www.readbyqxmd.com/read/27855694/cd274-promotes-cell-cycle-entry-of-leukemia-initiating-cells-through-jnk-cyclin-d2-signaling
#1
Xia Fang, Chiqi Chen, Fangzhen Xia, Zhuo Yu, Yaping Zhang, Feifei Zhang, Hao Gu, Jiangbo Wan, Xiaocui Zhang, Wei Weng, Cheng Cheng Zhang, Guo-Qiang Chen, Aibing Liang, Li Xie, Junke Zheng
BACKGROUND: CD274 (programmed death ligand 1, also known as B7H1) is expressed in both solid tumors and hematologic malignancies and is of critical importance for the escape of tumor cells from immune surveillance by inhibiting T cell function via its receptor, programmed death 1 (PD-1). Increasing evidence indicates that functional monoclonal antibodies of CD274 may potently enhance the antitumor effect in many cancers. However, the role of CD274 in leukemia-initiating cells (LICs) remains largely unknown...
November 17, 2016: Journal of Hematology & Oncology
https://www.readbyqxmd.com/read/27846391/instructive-role-of-mll-fusion-proteins-revealed-by-a-model-of-t-4-11-pro-b-acute-lymphoblastic-leukemia
#2
Shan Lin, Roger T Luo, Anetta Ptasinska, Jon Kerry, Salam A Assi, Mark Wunderlich, Toshihiko Imamura, Joseph J Kaberlein, Ahmad Rayes, Mark J Althoff, John Anastasi, Maureen M O'Brien, Amom Ruhikanta Meetei, Thomas A Milne, Constanze Bonifer, James C Mulloy, Michael J Thirman
The t(4;11)(q21;q23) fuses mixed-lineage leukemia (MLL) to AF4, the most common MLL-fusion partner. Here we show that MLL fused to murine Af4, highly conserved with human AF4, produces high-titer retrovirus permitting efficient transduction of human CD34(+) cells, thereby generating a model of t(4;11) pro-B acute lymphoblastic leukemia (ALL) that fully recapitulates the immunophenotypic and molecular aspects of the disease. MLL-Af4 induces a B ALL distinct from MLL-AF9 through differential genomic target binding of the fusion proteins leading to specific gene expression patterns...
November 14, 2016: Cancer Cell
https://www.readbyqxmd.com/read/27819671/protease-activated-receptor-1-inhibits-proliferation-but-enhances-leukemia-stem-cell-activity-in-acute-myeloid-leukemia
#3
S Goyama, M Shrestha, J Schibler, L Rosenfeldt, W Miller, E O'Brien, B Mizukawa, T Kitamura, J S Palumbo, J C Mulloy
Eradication of leukemia stem cells (LSCs) is the ultimate goal of treating acute myeloid leukemia (AML). We recently showed that the combined loss of Runx1/Cbfb inhibited the development of MLL-AF9-induced AML. However, c-Kit(+)/Gr-1(-) cells remained viable in Runx1/Cbfb-deleted cells, indicating that suppressing RUNX activity may not eradicate the most immature LSCs. In this study, we found upregulation of several hemostasis-related genes, including the thrombin-activatable receptor PAR-1 (protease-activated receptor-1), in Runx1/Cbfb-deleted MLL-AF9 cells...
November 7, 2016: Oncogene
https://www.readbyqxmd.com/read/27797721/zfx-modulates-the-growth-of-human-leukemic-cells-via-b4galt1
#4
Jie Wu, Lun Xiao, Haixia Zhou, Hong Liu, Yue Ge, Jing Yang, Yuanyuan Li, Depei Wu, Yun Zhao, Xiuyan Zhang
Zinc finger protein X-linked (ZFX) is a key regulator of both embryonic stem cells (ESCs) and hematopoietic stem cells (HSCs), which is required for both Notch intracellular domain (NotchIC)-induced acute T-cell leukemia and MLL-AF9-induced myeloid leukemia in mouse models. However, the role of ZFX and its underlying mechanism in human leukemic cells remain unclear yet, though accumulating data have demonstrated that ZFX is aberrantly expressed in various human tumors and plays an important role. Herein, we found that ZFX was aberrantly expressed in various human leukemic cell lines and primary cells from leukemia patients compared with control cells...
October 26, 2016: Acta Biochimica et Biophysica Sinica
https://www.readbyqxmd.com/read/27790998/extracellular-matrix-stiffness-causes-systematic-variations-in-proliferation-and-chemosensitivity-in-myeloid-leukemias
#5
Jae-Won Shin, David J Mooney
Extracellular matrix stiffness influences biological functions of some tumors. However, it remains unclear how cancer subtypes with different oncogenic mutations respond to matrix stiffness. In addition, the relevance of matrix stiffness to in vivo tumor growth kinetics and drug efficacy remains elusive. Here, we designed 3D hydrogels with physical parameters relevant to hematopoietic tissues and adapted them to a quantitative high-throughput screening format to facilitate mechanistic investigations into the role of matrix stiffness on myeloid leukemias...
October 25, 2016: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/27780967/modeling-human-mll-af9-translocated-acute-myeloid-leukemia-from-single-donors-reveals-ret-as-a-potential-therapeutic-target
#6
F Barabé, L Gil, M Celton, A Bergeron, V Lamontagne, É Roques, K Lagacé, A Forest, R Johnson, L Pécheux, J Simard, J Pelloux, A Bellemare-Pelletier, E Gagnon, J Hebert, S Cellot, B T Wilhelm
Acute myeloid leukemias (AML) result from a series of genetic events occurring in a stem or progenitor hematopoietic cell which gives rise to their clonal expansion and an impaired capacity to differentiate. To circumvent the genetic heterogeneity of AML patient cohorts, we have developed a model system, driven by the MLL-AF9 (MA9) oncogene, to generate multiple human leukemias using progenitor cells from a single healthy donor. Through stepwise RNA-sequencing data generated using this model and AML patients, we have identified consistent changes associated with MA9-driven leukemogenesis and demonstrate that no recurrent secondary mutations are required...
October 26, 2016: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
https://www.readbyqxmd.com/read/27756750/the-emt-regulator-zeb2-is-a-novel-dependency-of-human-and-murine-acute-myeloid-leukemia
#7
Hubo Li, Brenton G Mar, Huadi Zhang, Rishi V Puram, Francisca Vazquez, Barbara A Weir, William C Hahn, Benjamin Ebert, David Pellman
Acute myeloid leukemia (AML) is a heterogeneous disease with complex molecular pathophysiology. To systematically characterize AML's genetic dependencies, we conducted genome-scale shRNA screens in 17 AML cell lines and analyzed dependencies relative to parallel screens in 199 cell lines of other cancer types. We identified 353 genes specifically required for AML cell proliferation. To validate the in vivo relevance of genetic dependencies observed in human cell lines, we performed a secondary screen in a syngeneic murine AML model driven by the MLL-AF9 oncogenic fusion protein...
October 18, 2016: Blood
https://www.readbyqxmd.com/read/27607576/atg5-dependent-autophagy-contributes-to-the-development-of-acute-myeloid-leukemia-in-an-mll-af9-driven-mouse-model
#8
Qiang Liu, Longgui Chen, Jennifer M Atkinson, David F Claxton, Hong-Gang Wang
Acute myeloid leukemia (AML) is a hierarchical hematopoietic malignancy originating from leukemic stem cells (LSCs). Autophagy is a lysosomal degradation pathway that is hypothesized to be important for the maintenance of AML as well as contribute to chemotherapy response. Here we employ a mouse model of AML expressing the fusion oncogene MLL-AF9 and explore the effects of Atg5 deletion, a key autophagy protein, on the malignant transformation and progression of AML. Consistent with a transient decrease in colony-forming potential in vitro, the in vivo deletion of Atg5 in MLL-AF9-transduced bone marrow cells during primary transplantation prolonged the survival of recipient mice, suggesting that autophagy has a role in MLL-AF9-driven leukemia initiation...
September 8, 2016: Cell Death & Disease
https://www.readbyqxmd.com/read/27584789/impact-of-loss-of-bh3-only-proteins-on-the-development-and-treatment-of-mll-fusion-gene-driven-aml-in-mice
#9
Rebecca A Bilardi, Natasha S Anstee, Stefan P Glaser, Mikara Robati, Cassandra J Vandenberg, Suzanne Cory
Inhibition of the apoptosis pathway controlled by opposing members of the Bcl-2 protein family plays a central role in cancer development and resistance to therapy. To investigate how pro-apoptotic Bcl-2 homology domain 3 (BH3)-only proteins impact on acute myeloid leukemia (AML), we generated mixed lineage leukemia (MLL)-AF9 and MLL-ENL AMLs from BH3-only gene knockout mice. Disease development was not accelerated by loss of Bim, Puma, Noxa, Bmf, or combinations thereof; hence these BH3-only proteins are apparently ineffectual as tumor suppressors in this model...
2016: Cell Death & Disease
https://www.readbyqxmd.com/read/27556501/ralb-provides-critical-survival-signals-downstream-of-ras-in-acute-myeloid-leukemia
#10
Craig E Eckfeldt, Emily J Pomeroy, Robin D W Lee, Katherine S Hazen, Lindsey A Lee, Branden S Moriarity, David A Largaespada
Mutations that activate RAS proto-oncogenes and their effectors are common in acute myeloid leukemia (AML); however, efforts to therapeutically target Ras or its effectors have been unsuccessful, and have been hampered by an incomplete understanding of which effectors are required for AML proliferation and survival. We investigated the role of Ras effector pathways in AML using murine and human AML models. Whereas genetic disruption of NRAS(V12) expression in an NRAS(V12) and Mll-AF9-driven murine AML induced apoptosis of leukemic cells, inhibition of phosphatidylinositol-3-kinase (PI3K) and/or mitogen-activated protein kinase (MAPK) signaling did not reproduce this effect...
August 20, 2016: Oncotarget
https://www.readbyqxmd.com/read/27545619/structural-insights-into-histone-crotonyl-lysine-recognition-by-the-af9-yeats-domain
#11
Qiang Zhang, Lei Zeng, Chengcheng Zhao, Ying Ju, Tsuyoshi Konuma, Ming-Ming Zhou
Histone lysine acylations play an important role in the regulation of gene transcription in chromatin. Unlike histone acetyl-lysine, molecular recognition of a recently identified crotonyl-lysine mark is much less understood. Here, we report that the YEATS domain of AF9 preferentially binds crotonyl-lysine over acetyl-lysine in histone H3. Nuclear magnetic resonance structural analysis reveals that crotonyl-lysine of histone H3 lysine 18 is engulfed deep in an aromatic cage of the YEATS domain where the carbonyl oxygen of crotonyl-lysine forms a hydrogen bond with the backbone amide of protein residue Tyr78...
September 6, 2016: Structure
https://www.readbyqxmd.com/read/27462455/mll1-and-mll1-fusion-proteins-have-distinct-functions-in-regulating-leukemic-transcription-program
#12
Jing Xu, Li Li, Jie Xiong, Aaron denDekker, Andrew Ye, Hacer Karatas, Liu Liu, He Wang, Zhaohui S Qin, Shaomeng Wang, Yali Dou
Mixed lineage leukemia protein-1 (MLL1) has a critical role in human MLL1 rearranged leukemia (MLLr) and is a validated therapeutic target. However, its role in regulating global gene expression in MLLr cells, as well as its interplay with MLL1 fusion proteins remains unclear. Here we show that despite shared DNA-binding and cofactor interacting domains at the N terminus, MLL1 and MLL-AF9 are recruited to distinct chromatin regions and have divergent functions in regulating the leukemic transcription program...
2016: Cell Discovery
https://www.readbyqxmd.com/read/27411579/context-context-context-new-gene-programs-linked-to-bad-behavior-in-mll-af9-initiated-leukemia
#13
Tatsuro Watanabe, Patricia Ernst
In this issue of Cancer Cell, Stavropoulou et al. report that expression of the MLL-AF9 fusion results in acute myelogenous leukemia (AML) with different behaviors depending on cell context, which leads them to identify a transcriptional signature surprisingly resembling that of the epithelial-to-mesenchymal (EMT) transition, correlating with aggressiveness of disease.
July 11, 2016: Cancer Cell
https://www.readbyqxmd.com/read/27394641/modeling-human-leukemia-immunotherapy-in-humanized-mice
#14
Jinxing Xia, Zheng Hu, Satoshi Yoshihara, Yuying Li, Chun-Hui Jin, Shulian Tan, Wei Li, Qingfeng Chen, Megan Sykes, Yong-Guang Yang
The currently available human tumor xenograft models permit modeling of human cancers in vivo, but in immunocompromised hosts. Here we report a humanized mouse (hu-mouse) model made by transplantation of human fetal thymic tissue plus hematopoietic stem cells transduced with a leukemia-associated fusion gene MLL-AF9. In addition to normal human lymphohematopoietic reconstitution as seen in non-leukemic hu-mice, these hu-mice showed spontaneous development of B-cell acute lymphoblastic leukemia (B-ALL), which was transplantable to secondary recipients with an autologous human immune system...
August 2016: EBioMedicine
https://www.readbyqxmd.com/read/27374225/id2-and-e-proteins-orchestrate-the-initiation-and-maintenance-of-mll-rearranged-acute-myeloid-leukemia
#15
Margherita Ghisi, Lev Kats, Frederick Masson, Jason Li, Tobias Kratina, Eva Vidacs, Omer Gilan, Maria A Doyle, Andrea Newbold, Jessica E Bolden, Kirsten A Fairfax, Carolyn A de Graaf, Matthew Firth, Johannes Zuber, Ross A Dickins, Lynn M Corcoran, Mark A Dawson, Gabrielle T Belz, Ricky W Johnstone
E proteins and their antagonists, the Id proteins, are transcriptional regulators important for normal hematopoiesis. We found that Id2 acts as a key regulator of leukemia stem cell (LSC) potential in MLL-rearranged acute myeloid leukemia (AML). Low endogenous Id2 expression is associated with LSC enrichment while Id2 overexpression impairs MLL-AF9-leukemia initiation and growth. Importantly, MLL-AF9 itself controls the E-protein pathway by suppressing Id2 while directly activating E2-2 expression, and E2-2 depletion phenocopies Id2 overexpression in MLL-AF9-AML cells...
July 11, 2016: Cancer Cell
https://www.readbyqxmd.com/read/27344946/mll-af9-expression-in-hematopoietic-stem-cells-drives-a-highly-invasive-aml-expressing-emt-related-genes-linked-to-poor-outcome
#16
Vaia Stavropoulou, Susanne Kaspar, Laurent Brault, Mathijs A Sanders, Sabine Juge, Stefano Morettini, Alexandar Tzankov, Michelina Iacovino, I-Jun Lau, Thomas A Milne, Hélène Royo, Michael Kyba, Peter J M Valk, Antoine H F M Peters, Juerg Schwaller
To address the impact of cellular origin on acute myeloid leukemia (AML), we generated an inducible transgenic mouse model for MLL-AF9-driven leukemia. MLL-AF9 expression in long-term hematopoietic stem cells (LT-HSC) in vitro resulted in dispersed clonogenic growth and expression of genes involved in migration and invasion. In vivo, 20% LT-HSC-derived AML were particularly aggressive with extensive tissue infiltration, chemoresistance, and expressed genes related to epithelial-mesenchymal transition (EMT) in solid cancers...
July 11, 2016: Cancer Cell
https://www.readbyqxmd.com/read/27325891/targeting-mthfd2-in-acute-myeloid-leukemia
#17
Yana Pikman, Alexandre Puissant, Gabriela Alexe, Andrew Furman, Liying M Chen, Stacey M Frumm, Linda Ross, Nina Fenouille, Christopher F Bassil, Caroline A Lewis, Azucena Ramos, Joshua Gould, Richard M Stone, Daniel J DeAngelo, Ilene Galinsky, Clary B Clish, Andrew L Kung, Michael T Hemann, Matthew G Vander Heiden, Versha Banerji, Kimberly Stegmaier
Drugs targeting metabolism have formed the backbone of therapy for some cancers. We sought to identify new such targets in acute myeloid leukemia (AML). The one-carbon folate pathway, specifically methylenetetrahydrofolate dehydrogenase-cyclohydrolase 2 (MTHFD2), emerged as a top candidate in our analyses. MTHFD2 is the most differentially expressed metabolic enzyme in cancer versus normal cells. Knockdown of MTHFD2 in AML cells decreased growth, induced differentiation, and impaired colony formation in primary AML blasts...
June 27, 2016: Journal of Experimental Medicine
https://www.readbyqxmd.com/read/27312527/exploring-the-mechanism-how-af9-recognizes-and-binds-h3k9ac-by-molecular-dynamics-simulations-and-free-energy-calculations
#18
Quan Wang, Qing-Chuan Zheng, Hong-Xing Zhang
Histone acetylation is a very important regulatory mechanism in gene expression in the chromatin context. A new protein family-YEATS domains have been found as a novel histone acetylation reader, which could specific recognize the histone lysine acetylation. AF9 is an important one in the YEATS family. Focused on the AF9-H3K9ac (K9 acetylation) complex (ALY) (PDB code: 4TMP) and a serials of mutants, MUT (the acetyllsine of H3K9ac was mutated to lysine), F59A, G77A, and D103A, we applied molecular dynamics simulation and molecular mechanics Poisson-Boltzmann (MM-PBSA) free energy calculations to examine the role of AF9 protein in recognition interaction...
November 2016: Biopolymers
https://www.readbyqxmd.com/read/27310306/collaboration-of-mllt1-enl-polycomb-and-atm-for-transcription-and-genome-integrity
#19
Ayako Ui, Akira Yasui
Polycomb group (PcG) repress, whereas Trithorax group (TrxG) activate transcription for tissue development and cellular proliferation, and misregulation of these factors is often associated with cancer. ENL (MLLT1) and AF9 (MLLT3) are fusion partners of Mixed Lineage Leukemia (MLL), TrxG proteins, and are factors in Super Elongation Complex (SEC). SEC controls transcriptional elongation to release RNA polymerase II, paused around transcription start site. In MLL rearranged leukemia, several components of SEC have been found as MLL-fusion partners and the control of transcriptional elongation is misregulated leading to tumorigenesis in MLL-SEC fused Leukemia...
April 25, 2016: Nucleus
https://www.readbyqxmd.com/read/27308525/regulation-of-hematopoietic-progenitors-by-estrogens-as-a-basis-for-new-antileukemic-strategies
#20
Abel Sánchez-Aguilera, Simón Méndez-Ferrer
We recently reported that estrogens regulate survival, proliferation, and self-renewal of hematopoietic stem cells and progenitors via estrogen receptor-α activation. Through its proapoptotic effect on malignant progenitors, tamoxifen treatment blocks the development of JAK2 (V617F) -induced myeloproliferative neoplasms in mice and sensitizes MLL-AF9-induced leukemias to chemotherapy, without detrimental effects on normal hematopoiesis.
January 2016: Molecular & Cellular Oncology
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