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https://www.readbyqxmd.com/read/29650777/-mll-leukemia-induction-by-t-9-11-chromosomal-translocation-in-human-hematopoietic-stem-cells-using-genome-editing
#1
Corina Schneidawind, Johan Jeong, Dominik Schneidawind, In-Suk Kim, Jesús Duque-Afonso, Stephen Hon Kit Wong, Masayuki Iwasaki, Erin H Breese, James L Zehnder, Matthew Porteus, Michael L Cleary
Genome editing provides a potential approach to model de novo leukemogenesis in primary human hematopoietic stem and progenitor cells (HSPCs) through induction of chromosomal translocations by targeted DNA double-strand breaks. However, very low efficiency of translocations and lack of markers for translocated cells serve as barriers to their characterization and model development. Here, we used transcription activator-like effector nucleases to generate t(9;11) chromosomal translocations encoding MLL-AF9 and reciprocal AF9-MLL fusion products in CD34+ human cord blood cells...
April 24, 2018: Blood Advances
https://www.readbyqxmd.com/read/29649994/bile-acids-at-neutral-and-acidic-ph-induce-apoptosis-and-gene-cleavages-in-nasopharyngeal-epithelial-cells-implications-in-chromosome-rearrangement
#2
Sang-Nee Tan, Sai-Peng Sim
BACKGROUND: Chronic rhinosinusitis (CRS) increases the risk of developing nasopharyngeal carcinoma (NPC) while nasopharyngeal reflux is known to be one of the major aetiological factors of CRS. Bile acid (BA), the component of gastric duodenal contents, has been recognised as a carcinogen. BA-induced apoptosis was suggested to be involved in human malignancies. Cells have the potential and tendency to survive apoptosis. However, cells that evade apoptosis upon erroneous DNA repair may carry chromosome rearrangements...
April 12, 2018: BMC Cancer
https://www.readbyqxmd.com/read/29603337/cxcr4-blockade-improves-leukemia-eradication-by-allogeneic-lymphocyte-infusion
#3
Chun-Hui Jin, Yang Li, Jinxing Xia, Yuying Li, Mo Chen, Zheng Hu, Markus Y Mapara, Wei Li, Yong-Guang Yang
Persistent low levels of disease in bone marrow, an immunoprivileged tissue, are responsible for relapse following allogeneic hematopoietic cell transplantation. Using mouse models carrying primary human acute lymphoblast leukemia derived from MLL-AF9-overexpressing human hematopoietic stem cells, we demonstrate that allogeneic lymphocyte infusion (ALI)-mediated graft-vs.-leukemia effects selectively spare leukemia cells in the bone marrow. The resistance of leukemia cells to ALI within bone marrow is due to the immunosuppressive status of the tissue, as ALI achieved a significantly increased complete remission rate when leukemia cells were dislodged from bone marrow by treatment with a CXCR4 antagonist AMD3100...
March 30, 2018: American Journal of Hematology
https://www.readbyqxmd.com/read/29584620/jam3-maintains-leukemia-initiating-cell-self-renewal-through-lrp5-akt-%C3%AE-catenin-ccnd1-signaling
#4
Yaping Zhang, Fangzhen Xia, Xiaoye Liu, Zhuo Yu, Li Xie, Ligen Liu, Chiqi Chen, Haishan Jiang, Xiaoxin Hao, Xiaoxiao He, Feifei Zhang, Hao Gu, Jun Zhu, Haitao Bai, Cheng Cheng Zhang, Guo-Qiang Chen, Junke Zheng
Leukemia-initiating cells (LICs) are responsible for the initiation, development, and relapse of leukemia. The identification of novel therapeutic LIC targets is critical to curing leukemia. In this report, we reveal that junctional adhesion molecule 3 (JAM3) is highly enriched in both mouse and human LICs. Leukemogenesis is almost completely abrogated upon Jam3 deletion during serial transplantations in an MLL-AF9-induced murine acute myeloid leukemia model. In contrast, Jam3 deletion does not affect the functions of mouse hematopoietic stem cells...
March 26, 2018: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/29567837/the-brd3-et-domain-recognizes-a-short-peptide-motif-through-a-mechanism-that-is-conserved-across-chromatin-remodelers-and-transcriptional-regulators
#5
Dorothy C Wai, Taylor N Szyszka, Amy E Campbell, Cherry Kwong, Lorna E Wilkinson-White, Ana P G Silva, Jason K K Low, Ann H Kwan, Roland Gamsjaeger, James N Chalmers, Wayne M Patrick, Bin Lu, Christopher R Vakoc, Gerd Blobel, Joel P Mackay
Members of the bromodomain and extra-terminal domain (BET) family of proteins (bromodomain-containing (BRD) 2, 3, 4 and T) are widely expressed and highly conserved regulators of gene expression in eukaryotes. These proteins have been intimately linked to human disease and more than a dozen clinical trials are currently underway to test BET-protein inhibitors as modulators of cancer therapies. However, although it is clear that these proteins use their bromodomains to bind both histones and transcription factors bearing acetylated lysine residues, the molecular mechanisms by which BET-family proteins regulate gene expression are not well defined...
March 22, 2018: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/29551026/-characteristics-and-prognosis-in-adult-acute-myeloid-leukemia-patients-with-mll-gene-rearrangements
#6
X Y Gong, Y Wang, B C Liu, H Wei, C W Li, Q H Li, J W Zhao, C L Zhou, D Lin, K Q Liu, S N Wei, B F Gong, G J Zhang, Y T Liu, X L Zhao, Y Li, R X Gu, S W Qiu, Y C Mi, J X Wang
Objective: To analyze the clinical and laboratory characteristics, and prognosis of adult acute myeloid leukemia (AML) patients with MLL gene rearrangements. Methods: The medical records of 92 adult AML patients with MLL gene rearrangements from January 2010 to December 2016 were retrospectively analyzed. Results: 92 cases (6.5%) with MLL gene rearrangements were identified in 1 417 adult AML (Non-M(3)) patients, the median age of the patients was 35.5 years (15 to 64 years old) with an equal sex ratio, the median WBC were 21...
January 14, 2018: Zhonghua Xue Ye Xue za Zhi, Zhonghua Xueyexue Zazhi
https://www.readbyqxmd.com/read/29482582/camks-support-development-of-acute-myeloid-leukemia
#7
Xunlei Kang, Changhao Cui, Chen Wang, Guojin Wu, Heyu Chen, Zhigang Lu, Xiaoli Chen, Li Wang, Jie Huang, Huimin Geng, Meng Zhao, Zhengshan Chen, Markus Müschen, Huan-You Wang, Cheng Cheng Zhang
BACKGROUND: We recently identified the human leukocyte immunoglobulin-like receptor B2 (LILRB2) and its mouse ortholog-paired Ig-like receptor (PirB) as receptors for several angiopoietin-like proteins (Angptls). We also demonstrated that PirB is important for the development of acute myeloid leukemia (AML), but exactly how an inhibitory receptor such as PirB can support cancer development is intriguing. RESULTS: Here, we showed that the activation of Ca (2+)/calmodulin-dependent protein kinases (CAMKs) is coupled with PirB signaling in AML cells...
February 27, 2018: Journal of Hematology & Oncology
https://www.readbyqxmd.com/read/29482581/the-chromatin-remodeling-subunit-baf200-promotes-normal-hematopoiesis-and-inhibits-leukemogenesis
#8
Lulu Liu, Xiaoling Wan, Peipei Zhou, Xiaoyuan Zhou, Wei Zhang, Xinhui Hui, Xiujie Yuan, Xiaodan Ding, Ruihong Zhu, Guangxun Meng, Hui Xiao, Feng Ma, He Huang, Xianmin Song, Bin Zhou, Sidong Xiong, Yan Zhang
BACKGROUND: Adenosine triphosphate (ATP)-dependent chromatin remodeling SWI/SNF-like BAF and PBAF complexes have been implicated in the regulation of stem cell function and cancers. Several subunits of BAF or PBAF, including BRG1, BAF53a, BAF45a, BAF180, and BAF250a, are known to be involved in hematopoiesis. Baf200, a subunit of PBAF complex, plays a pivotal role in heart morphogenesis and coronary artery angiogenesis. However, little is known on the importance of Baf200 in normal and malignant hematopoiesis...
February 26, 2018: Journal of Hematology & Oncology
https://www.readbyqxmd.com/read/29477140/aurka-suppresses-leukemic-thp-1-cell-differentiation-through-inhibition-of-the-kdm6b-pathway
#9
Jin Woo Park, Hana Cho, Hyein Oh, Ji-Young Kim, Sang-Beom Seo
Aberrations in histone modifications are being studied in mixed-lineage leukemia (MLL)-AF9-driven acute myeloid leukemia (AML). In this study, we focused on the regulation of the differentiation of the MLL-AF9 type AML cell line THP-1. We observed that, upon phorbol 12-myristate 13-acetate (PMA) treatment, THP-1 cells differentiated into monocytes by down-regulating Aurora kinase A (AURKA), resulting in a reduction in H3S10 phosphorylation. We revealed that the AURKA inhibitor alisertib accelerates the expression of the H3K27 demethylase KDM6B, thereby dissociating AURKA and YY1 from the KDM6B promoter region...
February 23, 2018: Molecules and Cells
https://www.readbyqxmd.com/read/29453291/lsd1-inhibition-exerts-its-anti-leukemic-effect-by-recommissioning-pu-1-and-c-ebp%C3%AE-dependent-enhancers-in-aml
#10
Monica Cusan, Sheng F Cai, Helai P Mohammad, Andrei Krivtsov, Alan Chramiec, Evangelia Loizou, Matthew D Witkin, Kimberly N Smitheman, Daniel G Tenen, Min Ye, Britta Will, Ulrich Steidl, Ryan G Kruger, Ross L Levine, Hugh Y Rienhoff, Richard P Koche, Scott A Armstrong
Epigenetic regulators are recurrently mutated and aberrantly expressed in acute myeloid leukemia (AML). Targeted therapies designed to inhibit these chromatin-modifying enzymes, such as the histone demethylase lysine specific demethylase 1 (LSD1) and the histone methyltransferase DOT1L, have been developed as novel treatment modalities for these often refractory diseases. A common feature of many of these targeted agents is their ability to induce myeloid differentiation, suggesting that multiple paths toward a myeloid gene expression program can be engaged to relieve the differentiation blockade that is uniformly seen in AML...
February 16, 2018: Blood
https://www.readbyqxmd.com/read/29431698/mef2c-phosphorylation-is-required-for-chemotherapy-resistance-in-acute-myeloid-leukemia
#11
Fiona C Brown, Eric Still, Richard P Koche, Christina Y Yim, Sumiko Takao, Paolo Cifani, Casie Reed, Shehana Gunasekera, Scott B Ficarro, Peter Romanienko, Willie Mark, Craig McCarthy, Elisa de Stanchina, Mithat Gonen, Venkatraman Seshan, Patrick Bhola, Conor O'Donnell, Barbara Spitzer, Crystal Stutzke, Vincent-Philippe Lavallée, Josée Hébert, Andrei V Krivstov, Ari Melnick, Elisabeth M Paietta, Martin S Tallman, Anthony Letai, Guy Sauvageau, Gayle Pouliot, Ross Levine, Jarrod A Marto, Scott A Armstrong, Alex Kentsis
In acute myeloid leukemia, chemotherapy resistance remains prevalent and poorly understood. Using functional proteomics of patient AML specimens, we identified MEF2C S222 phosphorylation as a specific marker of primary chemoresistance. We found that Mef2c S222A/S222A knock-in mutant mice engineered to block MEF2C phosphorylation exhibited normal hematopoiesis, but were resistant to leukemogenesis induced by MLL-AF9. MEF2C phosphorylation was required for leukemia stem cell maintenance, and induced by MARK kinases in cells...
February 5, 2018: Cancer Discovery
https://www.readbyqxmd.com/read/29363207/heterogeneous-effects-of-m-csf-isoforms-on-the-progression-of-mll-af9-leukemia
#12
Rong Wang, Wenli Feng, Feifei Yang, Xiao Yang, Lina Wang, Chong Chen, Yuting Hu, Qian Ren, Guoguang Zheng
Macrophage colony-stimulating factor (M-CSF) regulates both malignant cells and microenvironmental cells. Its splicing isoforms show functional heterogeneity. However, their roles on leukemia have not been well established. Here, the expression of total M-CSF in patients with hematopoietic malignancies was analyzed. The roles of M-CSF isoforms on the progression of acute myeloid leukemia (AML) were studied by establishing MLL-AF9-induced mouse AML models with high level membrane-bound M-CSF (mM-CSF) or soluble M-CSF (sM-CSF)...
February 2018: Immunology and Cell Biology
https://www.readbyqxmd.com/read/29342133/a-myc-enhancer-cluster-regulates-normal-and-leukaemic-haematopoietic-stem-cell-hierarchies
#13
Carsten Bahr, Lisa von Paleske, Veli V Uslu, Silvia Remeseiro, Naoya Takayama, Stanley W Ng, Alex Murison, Katja Langenfeld, Massimo Petretich, Roberta Scognamiglio, Petra Zeisberger, Amelie S Benk, Ido Amit, Peter W Zandstra, Mathieu Lupien, John E Dick, Andreas Trumpp, François Spitz
The transcription factor Myc is essential for the regulation of haematopoietic stem cells and progenitors and has a critical function in haematopoietic malignancies. Here we show that an evolutionarily conserved region located 1.7 megabases downstream of the Myc gene that has previously been labelled as a 'super-enhancer' is essential for the regulation of Myc expression levels in both normal haematopoietic and leukaemic stem cell hierarchies in mice and humans. Deletion of this region in mice leads to a complete loss of Myc expression in haematopoietic stem cells and progenitors...
January 25, 2018: Nature
https://www.readbyqxmd.com/read/29320732/stabilization-of-nf-%C3%AE%C2%BAb-inducing-kinase-suppresses-mll-af9-induced-acute-myeloid-leukemia
#14
Yan Xiu, Qianze Dong, Qingchang Li, Fengyin Li, Nick Borcherding, Weizhou Zhang, Brendan Boyce, Hai-Hui Xue, Chen Zhao
Canonical NF-κB signaling is constitutively activated in acute myeloid leukemia (AML) stem cells and is required for maintenance of the self-renewal of leukemia stem cells (LSCs). However, any potential role for NF-κB non-canonical signaling in AML has been largely overlooked. Here, we report that stabilization of NF-κB-inducing kinase (NIK) suppresses AML. Mechanistically, stabilization of NIK activates NF-κB non-canonical signaling and represses NF-κB canonical signaling. In addition, stabilization of NIK-induced activation of NF-κB non-canonical signaling upregulates Dnmt3a and downregulates Mef2c, which suppresses and promotes AML development, respectively...
January 9, 2018: Cell Reports
https://www.readbyqxmd.com/read/29306107/leukemia-cells-impair-normal-hematopoiesis-and-induce-functionally-loss-of-hematopoietic-stem-cells-through-immune-cells-and-inflammation
#15
Ping Cui, Yuhua Zhang, Maoxiang Cui, Zhihong Li, Guang Ma, Rufeng Wang, Ning Wang, Shujuan Huang, Jie Gao
Bone marrow (BM) failure is often seen in leukemia patients, indicating an abnormal hematopoietic process. However, hematopoiesis in leukemic milieus is largely unknown. In the present study, we utilized one of the most frequent leukemogenic translocations MLL-AF9 to induce leukemia and investigated the hematopoiesis and the activity of hematopoietic stem and progenitor cells (HSPCs) in a leukemic milieu. We found that the phenotypes of the non-leukemic population in leukemic BM were drastically different than normal BM, including blockage of differentiation and a drastically reduced Lin-/Sca+/c-kit+ (LSK) population that contains all HSPCs in leukemic BM...
February 2018: Leukemia Research
https://www.readbyqxmd.com/read/29296851/agonistic-targeting-of-tlr1-tlr2-induces-p38-mapk-dependent-apoptosis-and-nf%C3%AE%C2%BAb-dependent-differentiation-of-aml-cells
#16
Mia Eriksson, Pablo Peña-Martínez, Ramprasad Ramakrishnan, Marion Chapellier, Carl Högberg, Gabriella Glowacki, Christina Orsmark-Pietras, Talía Velasco-Hernández, Vladimir Lj Lazarević, Gunnar Juliusson, Jörg Cammenga, James C Mulloy, Johan Richter, Thoas Fioretos, Benjamin L Ebert, Marcus Järås
Acute myeloid leukemia (AML) is associated with poor survival, and there is a strong need to identify disease vulnerabilities that might reveal new treatment opportunities. Here, we found that Toll-like receptor 1 (TLR1) and TLR2 are upregulated on primary AML CD34+ CD38- cells relative to corresponding normal bone marrow cells. Activating the TLR1/TLR2 complex by the agonist Pam3CSK4 in MLL-AF9 -driven human AML resulted in induction of apoptosis by p38 MAPK-dependent activation of Caspase 3 and myeloid differentiation in a NFκB-dependent manner...
October 24, 2017: Blood Advances
https://www.readbyqxmd.com/read/29296788/mll-af9-leukemias-are-sensitive-to-parp1-inhibitors-combined-with-cytotoxic-drugs
#17
Silvia Maifrede, Esteban Martinez, Margaret Nieborowska-Skorska, Daniela Di Marcantonio, Michael Hulse, Bac Viet Le, Huaqing Zhao, Katarzyna Piwocka, Italo Tempera, Stephen M Sykes, Tomasz Skorski
PARP1 is required for the maintenance of MLL-AF9 leukemias.PARP1 inhibitors enhance the therapeutic effect of cytotoxic drugs against MLL-AF9 leukemias.
August 22, 2017: Blood Advances
https://www.readbyqxmd.com/read/29240787/brd3-4-inhibition-and-flt3-ligand-deprivation-target-pathways-that-are-essential-for-the-survival-of-human-mll-af9-leukemic-cells
#18
Marco Carretta, Annet Z Brouwers-Vos, Matthieu Bosman, Sarah J Horton, Joost H A Martens, Edo Vellenga, Jan Jacob Schuringa
In the present work we aimed to identify targetable signaling networks in human MLL-AF9 leukemias. We show that MLL-AF9 cells critically depend on FLT3-ligand induced pathways as well as on BRD3/4 for their survival. We evaluated the in vitro and in vivo efficacy of the BRD3/4 inhibitor I-BET151 in various human MLL-AF9 (primary) models and patient samples and analyzed the transcriptome changes following treatment. To further understand the mode of action of BRD3/4 inhibition, we performed ChIP-seq experiments on the MLL-AF9 complex in THP1 cells and compared it to RNA-seq data of I-BET151 treated cells...
2017: PloS One
https://www.readbyqxmd.com/read/29164580/mir-564-inhibited-metastasis-and-proliferation-of-prostate-cancer-by-targeting-mllt3
#19
F-J Meng, F-M Meng, H-X Wu, X-F Cao
OBJECTIVE: MiR-564 has been discovered to be abnormally expressed in human malignancy. Two recent studies suggested that miR-564 plays a role in tumor inhibition in both lung and breast cancer. However, no evidence reported the mechanism and function of miR-564 in prostate cancer (PCa). PATIENTS AND METHODS: The PCa tissues and their adjacent normal tissues were collected from 50 PCa patients. Expressions of miR-564 in tissues and cells were evaluated with RT-qPCR...
November 2017: European Review for Medical and Pharmacological Sciences
https://www.readbyqxmd.com/read/29154208/characteristics-of-nk-cells-from-leukemic-microenvironment-in-mll-af9-induced-acute-myeloid-leukemia
#20
Feifei Yang, Rong Wang, Wenli Feng, Chong Chen, Xiao Yang, Lina Wang, Yuting Hu, Qian Ren, Guoguang Zheng
NK cells are indispensable components of tissue microenvironment and play vital in both innate and adaptive immunity. The activation and function of NK cells are affected by tumor microenvironments. NK cells are also important players in leukemic microenvironment. However, their characteristics in leukemic microenvironment, including maturation status, phenotype, subpopulations and functional roles especially immunoregulatory potential, have not been well established. Here, we studied these characteristics of NK cells in MLL-AF9 induced mouse acute myeloid leukemia (AML) model...
January 2018: Molecular Immunology
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