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https://www.readbyqxmd.com/read/29043883/structural-maintenance-of-chromosomes-4-is-required-for-leukemia-stem-cell-maintenance-in-mll-af9-induced-acute-myeloid-leukemia
#1
Luyun Peng, Yuanting Tang, Yingchi Zhang, Siqi Guo, Leiwen Peng, Lei Ye, Yuefang Wang, Yongmei Jiang
The gene, structural maintenance of chromosomes 4 (SMC4) plays important role in chromosomes condensing and mitotic sister chromatid segregation, which has been revealed in regulating multiple cancer development and carcinogenesis. However, the role of SMC4 in acute myeloid leukemia (AML) propagation and its function in regulation of leukemia stem cells (LSCs) is not yet clear. Using an MLL-AF9 induced AML mouse model, we demonstrated that down modulating of SMC4 expression could prolong the survival time of AML mice...
October 18, 2017: Leukemia & Lymphoma
https://www.readbyqxmd.com/read/29018079/setd2-alterations-impair-dna-damage-recognition-and-lead-to-resistance-to-chemotherapy-in-leukemia
#2
Brenton G Mar, S Haihua Chu, Josephine D Kahn, Andrei V Krivstov, Richard Koche, Cecilia A Castellano, Jacob L Kotlier, Rebecca L Zon, Marie E McConkey, Jonathan Chabon, Ryan Chappell, Peter V Grauman, James J Hsieh, Scott A Armstrong, Benjamin L Ebert
Mutations in SETD2, encoding the histone 3 lysine 36 trimethyltransferase, are enriched in relapsed acute lymphoblastic leukemia and MLL rearranged acute leukemia. We investigated the impact of SETD2 mutations on chemotherapy sensitivity in isogenic leukemia cell lines and in murine leukemia generated from a conditional knockout of Setd2SETD2 mutations led to resistance to DNA-damaging agents, cytarabine, 6-thioguanine, doxorubicin, and etoposide, but not to a non-DNA damaging agent, L-asparaginase. H3K36me3 localizes components of the DNA damage response pathway and SETD2 mutation impaired the DNA damage response (DDR), blunting apoptosis induced by cytotoxic chemotherapy...
October 10, 2017: Blood
https://www.readbyqxmd.com/read/28974232/the-stem-cell-factor-sall4-is-an-essential-transcriptional-regulator-in-mixed-lineage-leukemia-rearranged-leukemogenesis
#3
Lina Yang, Li Liu, Hong Gao, Jaya Pratap Pinnamaneni, Deepthi Sanagasetti, Vivek P Singh, Kai Wang, Megumi Mathison, Qianzi Zhang, Fengju Chen, Qianxing Mo, Todd Rosengart, Jianchang Yang
BACKGROUND: The stem cell factor spalt-like transcription factor 4 (SALL4) plays important roles in normal hematopoiesis and also in leukemogenesis. We previously reported that SALL4 exerts its effect by recruiting important epigenetic factors such as DNA methyltransferases DNMT1 and lysine-specific demethylase 1 (LSD1/KDM1A). Both of these proteins are critically involved in mixed lineage leukemia (MLL)-rearranged (MLL-r) leukemia, which has a very poor clinical prognosis. Recently, SALL4 has been further linked to the functions of MLL and its target gene homeobox A9 (HOXA9)...
October 3, 2017: Journal of Hematology & Oncology
https://www.readbyqxmd.com/read/28892146/murine-retrovirally-transduced-bone-marrow-engraftment-models-of-mll-fusion-driven-acute-myelogenous-leukemias-aml
#4
Matthew C Stubbs, Andrei V Krivtsov
MLL-rearranged leukemia represents approximately 5% to 10% of adult acute myelogenous leukemia (AML) and nearly half of all infant/pediatric acute leukemia cases. These leukemias have a poor prognosis, and there are no approved therapeutic options. The rearrangement in the MLL gene leads to aberrant expression of MLL-fusion proteins. These are transforming in murine bone marrow and, in particular, on stem cells and myeloid progenitors derived from bone marrow or fetal liver. The commonality of the MLL fusions is the in-frame fusion of 8 to 11 N-terminal exons of MLL1 (KMT2a) with the C-terminus of a partner fusion gene...
September 11, 2017: Current Protocols in Pharmacology
https://www.readbyqxmd.com/read/28886273/parpi-potentiates-with-current-conventional-therapy-in-mll-leukemia
#5
Lu Zhao, Chi Wai Eric So
Acute myeloid leukemias driven by MLL fusion proteins are commonly associated with poor prognosis and refractory treatment. Here, we provide evidence that olaparib can potentiate sensitivity of MLL leukemia cells to conventional chemotherapy and DNMT inhibitors offering new potential therapeutic strategies for MLL rearranged leukemias Using the primary mouse leukemia cells and human MLL-AF9 leukemic cell line, we demonstrate that treatment of MLL-AF9 leukemic cells with DNMT inhibitors or chemotherapies in combination with olaparib results in significant reduction in colony formation or cell growth while the single agent treatments had little impacts...
October 18, 2017: Cell Cycle
https://www.readbyqxmd.com/read/28741798/novel-orally-bioavailable-ezh1-2-dual-inhibitors-with-greater-antitumor-efficacy-than-an-ezh2-selective-inhibitor
#6
COMPARATIVE STUDY
Daisuke Honma, Osamu Kanno, Jun Watanabe, Junzo Kinoshita, Makoto Hirasawa, Emi Nosaka, Machiko Shiroishi, Takeshi Takizawa, Isao Yasumatsu, Takao Horiuchi, Akira Nakao, Keisuke Suzuki, Tomonori Yamasaki, Katsuyoshi Nakajima, Miho Hayakawa, Takanori Yamazaki, Ajay Singh Yadav, Nobuaki Adachi
Polycomb repressive complex 2 (PRC2) methylates histone H3 lysine 27 and represses gene expression to regulate cell proliferation and differentiation. Enhancer of zeste homolog 2 (EZH2) or its close homolog EZH1 functions as a catalytic subunit of PRC2, so there are two PRC2 complexes containing either EZH2 or EZH1. Tumorigenic functions of EZH2 and its synthetic lethality with some subunits of SWItch/Sucrose Non-Fermentable (SWI/SNF) chromatin remodeling complexes have been observed. However, little is known about the function of EZH1 in tumorigenesis...
October 2017: Cancer Science
https://www.readbyqxmd.com/read/28733386/mir-99-regulates-normal-and-malignant-hematopoietic-stem-cell-self-renewal
#7
Mona Khalaj, Carolien M Woolthuis, Wenhuo Hu, Benjamin H Durham, S Haihua Chu, Sarah Qamar, Scott A Armstrong, Christopher Y Park
The microRNA-99 (miR-99) family comprises a group of broadly conserved microRNAs that are highly expressed in hematopoietic stem cells (HSCs) and acute myeloid leukemia stem cells (LSCs) compared with their differentiated progeny. Herein, we show that miR-99 regulates self-renewal in both HSCs and LSCs. miR-99 maintains HSC long-term reconstitution activity by inhibiting differentiation and cell cycle entry. Moreover, miR-99 inhibition induced LSC differentiation and depletion in an MLL-AF9-driven mouse model of AML, leading to reduction in leukemia-initiating activity and improved survival in secondary transplants...
July 21, 2017: Journal of Experimental Medicine
https://www.readbyqxmd.com/read/28650479/aml1-eto-requires-enhanced-c-d-box-snorna-rnp-formation-to-induce-self-renewal-and-leukaemia
#8
Fengbiao Zhou, Yi Liu, Christian Rohde, Cornelius Pauli, Dennis Gerloff, Marcel Köhn, Danny Misiak, Nicole Bäumer, Chunhong Cui, Stefanie Göllner, Thomas Oellerich, Hubert Serve, Maria-Paz Garcia-Cuellar, Robert Slany, Jaroslaw P Maciejewski, Bartlomiej Przychodzen, Barbara Seliger, Hans-Ulrich Klein, Christoph Bartenhagen, Wolfgang E Berdel, Martin Dugas, Makoto Mark Taketo, Daneyal Farouq, Schraga Schwartz, Aviv Regev, Josée Hébert, Guy Sauvageau, Caroline Pabst, Stefan Hüttelmaier, Carsten Müller-Tidow
Leukaemogenesis requires enhanced self-renewal, which is induced by oncogenes. The underlying molecular mechanisms remain incompletely understood. Here, we identified C/D box snoRNAs and rRNA 2'-O-methylation as critical determinants of leukaemic stem cell activity. Leukaemogenesis by AML1-ETO required expression of the groucho-related amino-terminal enhancer of split (AES). AES functioned by inducing snoRNA/RNP formation via interaction with the RNA helicase DDX21. Similarly, global loss of C/D box snoRNAs with concomitant loss of rRNA 2'-O-methylation resulted in decreased leukaemia self-renewal potential...
July 2017: Nature Cell Biology
https://www.readbyqxmd.com/read/28646646/antileukemic-activity-and-cellular-effects-of-the-antimalarial-agent-artesunate-in-acute-myeloid-leukemia
#9
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...
August 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
#10
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
#11
Shan Lin, Roger T Luo, Mahesh Shrestha, Michael J Thirman, James C Mulloy
Chromosome rearrangements involving the mixed-lineage leukemia gene (MLL) create MLL-fusion proteins, which could drive both acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (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 (HSPCs) expressing MLL-AF9 or MLL-Af4 into immunodeficient NSGS mice, which strongly promote myeloid development...
August 17, 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
#12
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...
August 3, 2017: Blood
https://www.readbyqxmd.com/read/28609655/mll2-not-mll1-plays-a-major-role-in-sustaining-mll-rearranged-acute-myeloid-leukemia
#13
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
#14
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
#15
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
#16
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
#17
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/28454357/expression-regulation-and-function-of-mir-495-in-healthy-and-tumor-tissues
#18
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
#19
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
#20
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
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