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https://www.readbyqxmd.com/read/28500307/alox5-exhibits-anti-tumor-and-drug-sensitizing-effects-in-mll-rearranged-leukemia
#1
Yungui Wang, Jennifer R Skibbe, Chao Hu, Lei Dong, Kyle Ferchen, Rui Su, Chenying Li, Hao Huang, Hengyou Weng, Huilin Huang, Xi Qin, Jie Jin, Jianjun Chen, Xi Jiang
MLL-rearranged acute myeloid leukemia (AML) remains a fatal disease with a high rate of relapse and therapeutic failure due to chemotherapy resistance. In analysis of our Affymetrix microarray profiling and chromatin immunoprecipitation (ChIP) assays, we found that ALOX5 is especially down-regulated in MLL-rearranged AML, via transcription repression mediated by Polycomb repressive complex 2 (PRC2). Colony forming/replating and bone marrow transplantation (BMT) assays showed that Alox5 exhibited a moderate anti-tumor effect both in vitro and in vivo...
May 12, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28462918/targeting-hdac3-new-partner-protein-of-akt-in-the-reversal-of-chemo-resistance-in-acute-myeloid-leukemia-via-dna-damage-response
#2
Jun Long, W Y Fang, Li Chang, W H Gao, Yan Shen, M Y Jia, Y X Zhang, Y Wang, H B Dou, W J Zhang, J Zhu, A B Liang, J M Li, J Hu
Resistance to cytotoxic chemotherapy drugs remains as the major cause of treatment failure in acute myeloid leukemia. Histone deacetylases are important regulators to maintain chromatin structure and control DNA damage; nevertheless, how each HDAC regulates genome stability remains unclear, especially under genome stress conditions. Here, we identified a mechanism by which HDAC3 regulates DNA damage repair and mediates resistance to chemotherapy drugs. In addition to inducing DNA damage, chemotherapy drugs trigger upregulation of HDAC3 expression in leukemia cells...
May 2, 2017: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
https://www.readbyqxmd.com/read/28456746/genetically-engineered-mesenchymal-stromal-cells-producing-il3-and-tpo-to-further-improve-human-scaffold-based-xenograft-models
#3
M Carretta, B de Boer, J Jaques, A Antonelli, S J Horton, H Yuan, J D de Bruijn, R W J Groen, E Vellenga, J J Schuringa
Recently, NOD-SCID IL2Rγ(-/-) (NSG) mice were implanted with human mesenchymal stromal cells (MSCs) in the presence of ceramic scaffolds or matrigel in order to mimic the human bone marrow (BM) microenvironment. This approach allowed the engraftment of leukemic samples that failed to engraft in NSG mice without humanized niches and resulted in a better preservation of leukemic stem cell self-renewal properties [1-3]. To further improve our humanized niche scaffold model, we genetically engineered human MSCs to secrete human IL3 and TPO...
April 26, 2017: Experimental Hematology
https://www.readbyqxmd.com/read/28454357/expression-regulation-and-function-of-mir-495-in-healthy-and-tumor-tissues
#4
Hongli Chen, Xiaman Wang, Ju Bai, Aili He
MicroRNA-495 (miR-495) is a small non-coding RNA encoded by a gene located on chromosome 14 (14q32.31). Its expression is regulated by the transcription factors EF12 and EF47, in addition to promoter methylation status and the fusion oncoprotein mixed-lineage leukemia-AF9. Previous studies suggest that miR-495 is involved in various developmental, immunological and inflammatory processes in healthy tissue, and in the proliferation, invasion, metastasis and drug resistance of cancer cells. The role miR-495 serves in tumors is controversial...
April 2017: Oncology Letters
https://www.readbyqxmd.com/read/28412727/znf521-sustains-the-differentiation-block-in-mll-rearranged-acute-myeloid-leukemia
#5
Giuseppe Germano, Giulia Morello, Sanja Aveic, Marica Pinazza, Sonia Minuzzo, Chiara Frasson, Luca Persano, Paolo Bonvini, Giampietro Viola, Silvia Bresolin, Claudia Tregnago, Maddalena Paganin, Martina Pigazzi, Stefano Indraccolo, Giuseppe Basso
Zinc finger protein 521 (ZNF521) is a multiple zinc finger transcription factor and a strong candidate as regulator of hematopoietic stem cell homeostasis. Recently, independent gene expression profile studies have evidenced a positive correlation between ZNF521 mRNA overexpression and MLL-rearranged acute myeloid leukemia (AML), leaving open the question on the role of ZNF521 in this subtype of leukemia. In this study, we sought to analyze the effect of ZNF521 depletion on MLL-rearranged AML cell lines and MLL-AF9 xenograft primary cells...
April 18, 2017: Oncotarget
https://www.readbyqxmd.com/read/28411381/pbx3-is-essential-for-leukemia-stem-cell-maintenance-in-mll-rearranged-leukemia
#6
Huidong Guo, Yajing Chu, Le Wang, Xing Chen, Yangpeng Chen, Hui Cheng, Lei Zhang, Yuan Zhou, Feng-Chun Yang, Tao Cheng, Mingjiang Xu, Xiaobing Zhang, Jianfeng Zhou, Weiping Yuan
Interaction of HOXA9/MEIS1/PBX3 is responsible for hematopoietic system transformation in MLL-rearranged (MLL-r) leukemia. Of these genes, HOXA9 has been shown to be critical for leukemia cell survival, while MEIS1 has been identified as an essential regulator for leukemia stem cell (LSC) maintenance. Although significantly high expression of PBX3 was observed in clinical acute myeloid leukemia (AML) samples, the individual role of PBX3 in leukemia development is still largely unknown. In this study, we explored the specific role of PBX3 and its associated regulatory network in leukemia progression...
April 15, 2017: International Journal of Cancer. Journal International du Cancer
https://www.readbyqxmd.com/read/28399691/effect-of-aldosterone-on-cochlear-af9-expression-and-hearing-in-guinea-pig
#7
Li Qin, Biyun Zhang, Qianying Wang, Duanchao Li, Xiaoli Luo, Shixun Zhong
CONCLUSIONS: Af9 protein in cochlea may be closely related to endolymph regulation by aldosterone and thus may be involved in pathogenesis of endolymphatic hydrops (EH). OBJECTIVES: EH is the pathological characteristic of Ménière's disease (MD). Aldosterone could induce EH, but its relationship with MD is still controversial. The aim of the present study is to investigate the Af9 protein expression in guinea pig cochlea and regulation of Af9 expression and cochlear function by aldosterone...
April 11, 2017: Acta Oto-laryngologica
https://www.readbyqxmd.com/read/28394257/cooperative-gene-activation-by-af4-and-dot1l-drives-mll-rearranged-leukemia
#8
Hiroshi Okuda, Boban Stanojevic, Akinori Kanai, Takeshi Kawamura, Satoshi Takahashi, Hirotaka Matsui, Akifumi Takaori-Kondo, Akihiko Yokoyama
The eleven-nineteen leukemia (ENL) protein family, composed of ENL and AF9, is a common component of 3 transcriptional modulators: AF4-ENL-P-TEFb complex (AEP), DOT1L-AF10-ENL complex (referred to as the DOT1L complex) and polycomb-repressive complex 1 (PRC1). Each complex associates with chromatin via distinct mechanisms, conferring different transcriptional properties including activation, maintenance, and repression. The mixed-lineage leukemia (MLL) gene often fuses with ENL and AF10 family genes in leukemia...
May 1, 2017: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/28282266/autophagy-is-dispensable-for-kmt2a-mll-mllt3-af9-aml-maintenance-and-anti-leukemic-effect-of-chloroquine
#9
Xiaoyi Chen, Jason Clark, Mark Wunderlich, Cuiqing Fan, Ashley Davis, Song Chen, Jun-Lin Guan, James C Mulloy, Ashish Kumar, Yi Zheng
Recently, macroautophagy/autophagy has emerged as a promising target in various types of solid tumor treatment. However, the impact of autophagy on acute myeloid leukemia (AML) maintenance and the validity of autophagy as a viable target in AML therapy remain unclear. Here we show that Kmt2a/Mll-Mllt3/Af9 AML (MA9-AML) cells have high autophagy flux compared with normal bone marrow cells, but autophagy-specific targeting, either through Rb1cc1-disruption to abolish autophagy initiation, or via Atg5-disruption to prevent phagophore (the autophagosome precursor) membrane elongation, does not affect the growth or survival of MA9-AML cells, either in vitro or in vivo...
February 15, 2017: Autophagy
https://www.readbyqxmd.com/read/28241141/enl-links-histone-acetylation-to-oncogenic-gene-expression-in-acute-myeloid-leukaemia
#10
Liling Wan, Hong Wen, Yuanyuan Li, Jie Lyu, Yuanxin Xi, Takayuki Hoshii, Julia K Joseph, Xiaolu Wang, Yong-Hwee E Loh, Michael A Erb, Amanda L Souza, James E Bradner, Li Shen, Wei Li, Haitao Li, C David Allis, Scott A Armstrong, Xiaobing Shi
Cancer cells are characterized by aberrant epigenetic landscapes and often exploit chromatin machinery to activate oncogenic gene expression programs. Recognition of modified histones by 'reader' proteins constitutes a key mechanism underlying these processes; therefore, targeting such pathways holds clinical promise, as exemplified by the development of bromodomain and extra-terminal (BET) inhibitors. We recently identified the YEATS domain as an acetyl-lysine-binding module, but its functional importance in human cancer remains unknown...
March 9, 2017: Nature
https://www.readbyqxmd.com/read/28210006/a-novel-lsd1-inhibitor-ncd38-ameliorates-mds-related-leukemia-with-complex-karyotype-by-attenuating-leukemia-programs-via-activating-super-enhancers
#11
N Sugino, M Kawahara, G Tatsumi, A Kanai, H Matsui, R Yamamoto, Y Nagai, S Fujii, Y Shimazu, M Hishizawa, T Inaba, A Andoh, T Suzuki, A Takaori-Kondo
Lysine-specific demethylase 1 (LSD1) regulates gene expression by affecting histone modifications and is a promising target for acute myeloid leukemia (AML) with specific genetic abnormalities. Novel LSD1 inhibitors, NCD25 and NCD38, inhibited growth of MLL-AF9 leukemia as well as erythroleukemia, megakaryoblastic leukemia and myelodysplastic syndromes (MDS) overt leukemia cells in the concentration range that normal hematopoiesis was spared. NCD25 and NCD38 invoked the myeloid development programs, hindered the MDS and AML oncogenic programs, and commonly upregulated 62 genes in several leukemia cells...
February 17, 2017: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
https://www.readbyqxmd.com/read/28202522/histone-acetyltransferase-activity-of-mof-is-required-for-mll-af9-leukemogenesis
#12
Daria G Valerio, Haiming Xu, Chun-Wei Chen, Takayuki Hoshii, Meghan E Eisold, Christopher Delaney, Monica Cusan, Aniruddha J Deshpande, Chun-Hao Huang, Amaia Lujambio, YuJun George Zheng, Johannes Zuber, Tej K Pandita, Scott W Lowe, Scott A Armstrong
Chromatin-based mechanisms offer therapeutic targets in acute myeloid leukemia (AML) that are of great current interest. In this study, we conducted an RNAi-based screen to identify druggable chromatin regulator-based targets in leukemias marked by oncogenic rearrangements of the MLL gene. In this manner, we discovered the H4K16 histone acetyltransferase (HAT) MOF to be important for leukemia cell growth. Conditional deletion of Mof in a mouse model of MLL-AF9-driven leukemogenesis reduced tumor burden and prolonged host survival...
February 15, 2017: Cancer Research
https://www.readbyqxmd.com/read/28186757/thieno-3-2-b-pyrrole-5-carboxamides-as-new-reversible-inhibitors-of-histone-lysine-demethylase-kdm1a-lsd1-part-2-structure-based-drug-design-and-structure-activity-relationship
#13
Paola Vianello, Luca Sartori, Federica Amigoni, Anna Cappa, Giovanni Fagá, Raimondo Fattori, Elena Legnaghi, Giuseppe Ciossani, Andrea Mattevi, Giuseppe Meroni, Loris Moretti, Valentina Cecatiello, Sebastiano Pasqualato, Alessia Romussi, Florian Thaler, Paolo Trifiró, Manuela Villa, Oronza A Botrugno, Paola Dessanti, Saverio Minucci, Stefania Vultaggio, Elisa Zagarrí, Mario Varasi, Ciro Mercurio
The balance of methylation levels at histone H3 lysine 4 (H3K4) is regulated by KDM1A (LSD1). KDM1A is overexpressed in several tumor types, thus representing an emerging target for the development of novel cancer therapeutics. We have previously described ( Part 1, DOI 10.1021.acs.jmedchem.6b01018 ) the identification of thieno[3,2-b]pyrrole-5-carboxamides as novel reversible inhibitors of KDM1A, whose preliminary exploration resulted in compound 2 with biochemical IC50 = 160 nM. We now report the structure-guided optimization of this chemical series based on multiple ligand/KDM1A-CoRest cocrystal structures, which led to several extremely potent inhibitors...
February 27, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28179274/mouse-models-of-mll-leukemia-recapitulating-the-human-disease
#14
REVIEW
Thomas A Milne
Chromosome translocations involving the mixed lineage leukemia (MLL) gene fuse it in frame with multiple partner genes creating novel fusion proteins (MLL-FPs) that cause aggressive acute leukemias in humans. Animal models of human disease are important for the exploration of underlying disease mechanisms as well as for testing novel therapeutic approaches. Patients carrying MLL-FPs have very few cooperating mutations, making MLL-FP driven leukemias ideal for animal modeling. The fact that the MLL-FP is the main driver mutation has allowed for a wide range of different experimental model systems designed to explore different aspects of MLL-FP leukemogenesis...
April 20, 2017: Blood
https://www.readbyqxmd.com/read/28126968/cd244-maintains-the-proliferation-ability-of-leukemia-initiating-cells-through-shp-2-p27kip1-signaling
#15
Feifei Zhang, Xiaoye Liu, Chiqi Chen, Jun Zhu, Zhuo Yu, Jingjing Xie, Li Xie, Haitao Bai, Yaping Zhang, Xia Fang, Hao Gu, Chun Wang, Wei Weng, Cheng Cheng Zhang, Guo-Qiang Chen, Aibing Liang, Junke Zheng
Targeting leukemia initiating cells is considered to be an effective way to cure leukemia, for which it is critical to identify novel therapeutic targets. Herein, we demonstrate that CD244, which is initially reported as a key regulator for NK cells, is highly expressed on both mouse and human leukemia initiating cells. Upon CD244 knockdown, human leukemia cell lines and primary leukemia cells have markedly impaired proliferation abilities both in vitro and in vivo. Interestingly, the repopulation ability of both mouse and human hematopoietic stem cells is not impaired upon CD244 knockdown...
January 25, 2017: Haematologica
https://www.readbyqxmd.com/read/28114278/mll-af9-and-mll-af4-oncofusion-proteins-bind-a-distinct-enhancer-repertoire-and-target-the-runx1-program-in-11q23-acute-myeloid-leukemia
#16
K H M Prange, A Mandoli, T Kuznetsova, S-Y Wang, A M Sotoca, A E Marneth, B A van der Reijden, H G Stunnenberg, J H A Martens
In 11q23 leukemias, the N-terminal part of the mixed lineage leukemia (MLL) gene is fused to >60 different partner genes. In order to define a core set of MLL rearranged targets, we investigated the genome-wide binding of the MLL-AF9 and MLL-AF4 fusion proteins and associated epigenetic signatures in acute myeloid leukemia (AML) cell lines THP-1 and MV4-11. We uncovered both common as well as specific MLL-AF9 and MLL-AF4 target genes, which were all marked by H3K79me2, H3K27ac and H3K4me3. Apart from promoter binding, we also identified MLL-AF9 and MLL-AF4 binding at specific subsets of non-overlapping active distal regulatory elements...
January 23, 2017: Oncogene
https://www.readbyqxmd.com/read/28053194/mir-125b-promotes-mll-af9-driven-murine-acute-myeloid-leukemia-involving-a-vegfa-mediated-non-cell-intrinsic-mechanism
#17
Jun Liu, Bo Guo, Zhuo Chen, Nayi Wang, Michelina Iacovino, Jijun Cheng, Christine Roden, Wen Pan, Sajid Khan, Suning Chen, Michael Kyba, Rong Fan, Shangqin Guo, Jun Lu
The hematopoietic stem cell-enriched miR-125 family microRNAs (miRNAs) are critical regulators of hematopoiesis. Overexpression of miR-125a or miR-125b is frequent in human acute myeloid leukemia (AML), and the overexpression of these miRNAs in mice leads to expansion of hematopoietic stem cells accompanied by perturbed hematopoiesis with mostly myeloproliferative phenotypes. However, whether and how miR-125 family miRNAs cooperate with known AML oncogenes in vivo, and how the resultant leukemia is dependent on miR-125 overexpression, are not well understood...
March 16, 2017: Blood
https://www.readbyqxmd.com/read/27855694/cd274-promotes-cell-cycle-entry-of-leukemia-initiating-cells-through-jnk-cyclin-d2-signaling
#18
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
#19
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
#20
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...
May 4, 2017: Oncogene
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