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https://www.readbyqxmd.com/read/28646646/antileukemic-activity-and-cellular-effects-of-the-antimalarial-agent-artesunate-in-acute-myeloid-leukemia
#1
Bijender Kumar, Arjun Kalvala, Su Chu, Steven Rosen, Stephen J Forman, Guido Marcucci, Ching-Cheng Chen, Vinod Pullarkat
The artimisinins are a class of antimalarial compounds whose antiparasitic activity is mediated by induction of reactive oxygen species (ROS). Herein, we report that among the artimisinins, artesunate (ARTS), an orally bioavailable compound has the most potent antileukemic activity in AML models and primary patients' blasts. ARTS was most cytotoxic to the FLT3-ITD+ AML MV4-11 and MOLM-13 cells (IC50 values of 1.1 and 0.82μM respectively), inhibited colony formation in primary AML and MDS cells and augmented cytotoxicity of chemotherapeutics...
May 10, 2017: Leukemia Research
https://www.readbyqxmd.com/read/28646565/complete-molecular-remission-in-relapsed-and-refractory-acute-myeloid-leukaemia-with-mll-af9-treated-with-chidamide-based-chemotherapy
#2
Y Lun, J-J Yang, Y Wu
WHAT IS KNOWN AND OBJECTIVE: The mixed lineage leukaemia (MLL) gene translocations are found in approximately 10% of adults with acute myeloid leukaemia (AML) and are markers of poor prognosis. As the best reported response in relapsed and refractory MLL-rearranged AML is around 40%, reinduction treatment is very challenging for those patients. CASE DESCRIPTION: We report a case of relapsed and refractory AML with MLL-AF9, who did not respond to FLAG (fludarabine, cytarabine, granulocyte colony stimulating factor) regimen reinduction treatment, but achieved complete response and molecular remission after chidamide-based chemotherapy...
June 23, 2017: Journal of Clinical Pharmacy and Therapeutics
https://www.readbyqxmd.com/read/28637661/the-full-transforming-capacity-of-mll-af4-is-interlinked-with-lymphoid-lineage-commitment
#3
Shan Lin, Roger T Luo, Mahesh Shrestha, Michael J Thirman, James C Mulloy
Chromosome rearrangements involving mixed-lineage leukemia gene (MLL) create MLL-fusion proteins, which could drive both acute lymphoblastic and myeloid leukemia (ALL and AML). The lineage decision of MLL-fusion leukemia is influenced by the fusion partner and microenvironment. To investigate the interplay of fusion proteins and microenvironment in lineage choice, we transplanted human hematopoietic stem and progenitor cells (HSPC) expressing MLL-AF9 or MLL-Af4 into immunodeficient NSGS mice, which strongly promote myeloid development...
June 21, 2017: Blood
https://www.readbyqxmd.com/read/28615219/zfp521-regulates-murine-hematopoietic-stem-cell-function-and-facilitates-mll-af9-leukemogenesis-in-mouse-and-human-cells
#4
Brian S Garrison, Adrian P Rybak, Isabel Beerman, Balthasar Heesters, Francois E Mercier, David T Scadden, David Bryder, Roland Baron, Derrick J Rossi
The concept that tumor-initiating cells can co-opt the self-renewal program of endogenous stem cells as a means of enforcing their unlimited proliferative potential is widely accepted, yet identification of specific factors that regulate self-renewal of normal and cancer stem cells remains limited. Using a comparative transcriptomic approach, we identify ZNF521/Zfp521 as a conserved hematopoietic stem cell (HSC)-enriched transcription factor in human and murine hematopoiesis, whose function in HSC biology remains elusive...
June 14, 2017: Blood
https://www.readbyqxmd.com/read/28609655/mll2-not-mll1-plays-a-major-role-in-sustaining-mll-rearranged-acute-myeloid-leukemia
#5
Yufei Chen, Konstantinos Anastassiadis, Andrea Kranz, A Francis Stewart, Kathrin Arndt, Claudia Waskow, Akihiko Yokoyama, Kenneth Jones, Tobias Neff, Yoo Lee, Patricia Ernst
The MLL1 histone methyltransferase gene undergoes many distinct chromosomal rearrangements to yield poor-prognosis leukemia. The remaining wild-type allele is most commonly, but not always, retained. To what extent the wild-type allele contributes to leukemogenesis is unclear. Here we show, using rigorous, independent animal models, that endogenous MLL1 is dispensable for MLL-rearranged leukemia. Potential redundancy was addressed by co-deleting the closest paralog, Mll2. Surprisingly, Mll2 deletion alone had a significant impact on survival of MLL-AF9-transformed cells, and additional Mll1 loss further reduced viability and proliferation...
June 12, 2017: Cancer Cell
https://www.readbyqxmd.com/read/28592067/-combination-of-pp242-and-dasatinib-suppresses-the-progression-of-acute-myeloid-leukemia-in-a-mouse-model
#6
Y H Qu, H T Liu, F C He
Objective: To establish the acute myeloid leukemia (AML) mouse model, and to preliminarily investigate the efficiency of dasatinib, a tryosine kinase inhibitor, and PP242, an inhibitor of PI3K/Akt/mTOR signaling pathway in the development of AML. Methods: The lineage(-) (Lin(-)) cells of C57BL/6J were transduced with retrovirus carrying MSCV-MLL-AF9-IRES-GFP fusion gene. The transduced cells were transplanted into lethally irradiated recipient mice to induce AML, and then the AML mouse model were established...
May 30, 2017: Zhonghua Yi Xue za Zhi [Chinese medical journal]
https://www.readbyqxmd.com/read/28500307/alox5-exhibits-anti-tumor-and-drug-sensitizing-effects-in-mll-rearranged-leukemia
#7
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
#8
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-produce-il-3-and-tpo-to-further-improve-human-scaffold-based-xenograft-models
#9
Marco Carretta, Bauke de Boer, Jenny Jaques, Antonella Antonelli, Sarah J Horton, Huipin Yuan, Joost D de Bruijn, Richard W J Groen, Edo Vellenga, Jan Jacob Schuringa
Recently, NOD-SCID IL2Rγ(-/-) (NSG) mice were implanted with human mesenchymal stromal cells (MSCs) in the presence of ceramic scaffolds or Matrigel 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. To further improve our humanized niche scaffold model, we genetically engineered human MSCs to secrete human interleukin-3 (IL-3) and thrombopoietin (TPO)...
July 2017: Experimental Hematology
https://www.readbyqxmd.com/read/28412727/znf521-sustains-the-differentiation-block-in-mll-rearranged-acute-myeloid-leukemia
#10
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
#11
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...
July 15, 2017: International Journal of Cancer. Journal International du Cancer
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
#12
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
#13
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
#14
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
#15
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-p27-kip1-signaling
#16
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 was initially reported as a key regulator for natural killer 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...
April 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
#17
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...
June 8, 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
#18
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
#19
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
#20
COMMENT
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
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