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https://www.readbyqxmd.com/read/28447382/quantitative-proteomic-analysis-of-ezh2-inhibition-in-acute-myeloid-leukemia-reveals-the-targets-and-pathways-that-precede-the-induction-of-cell-death
#1
Jarrod J Sandow, Giuseppe Infusini, Aliaksei Z Holik, Gabriela Brumatti, Tessa V Averink, Paul G Ekert, Andrew I Webb
PURPOSE: Chromosomal translocation of the Mixed Lineage Leukemia (MLL) locus generates fusion proteins that drive acute myeloid leukemia (AML) resulting in atypical histone methyltransferase activity and alterations in the epigenetic regulation of gene expression. Targeting histone regulators, such as Enhancer of Zeste Homologue 2 (EZH2), has shown promise in AML. Profiling differential protein expression following inhibition of epigenetic regulators in AML may help to identify novel targets for therapeutics...
April 26, 2017: Proteomics. Clinical Applications
https://www.readbyqxmd.com/read/28446316/-prognostic-value-of-recurrent-molecular-genetics-and-epigenetics-abnormity-in-t-lymphoblastic-lymphoma-leukemia-review
#2
Wei Guan, Yu Jing, Li Yu
T lymphoblastic lymphoma / leukemia is a strong invasive and has a high incidence of various molecular genetic abnormalities. The NOTCH1 / FBXW7 mutation is one of the most common mutations, and related with good prognosis in T-LBL / ALL. PTEN mutation, a poor prognostic factor, could be overcome by NOTCH1 mutations in pediatric patients to some extent. Patients with MLL gene abnormality and loss of heterozygosity 6q have worse prognosis than those with normal karyotype. The incidence of MLL gene abnormality, RUNX1 mutation and DNMT3A mutation in early precursor T-lymphoblastic leukemia was higher than that of other mature subtypes, which could be used as risk stratification factors...
April 2017: Zhongguo Shi Yan Xue Ye Xue za Zhi
https://www.readbyqxmd.com/read/28436985/functional-screen-of-msi2-interactors-identifies-an-essential-role-for-syncrip-in-myeloid-leukemia-stem-cells
#3
Ly P Vu, Camila Prieto, Elianna M Amin, Sagar Chhangawala, Andrei Krivtsov, M Nieves Calvo-Vidal, Timothy Chou, Arthur Chow, Gerard Minuesa, Sun Mi Park, Trevor S Barlowe, James Taggart, Patrick Tivnan, Raquel P Deering, Lisa P Chu, Jeong-Ah Kwon, Cem Meydan, Javier Perales-Paton, Arora Arshi, Mithat Gönen, Christopher Famulare, Minal Patel, Elisabeth Paietta, Martin S Tallman, Yuheng Lu, Jacob Glass, Francine E Garret-Bakelman, Ari Melnick, Ross Levine, Fatima Al-Shahrour, Marcus Järås, Nir Hacohen, Alexia Hwang, Ralph Garippa, Christopher J Lengner, Scott A Armstrong, Leandro Cerchietti, Glenn S Cowley, David Root, John Doench, Christina Leslie, Benjamin L Ebert, Michael G Kharas
The identity of the RNA-binding proteins (RBPs) that govern cancer stem cells remains poorly characterized. The MSI2 RBP is a central regulator of translation of cancer stem cell programs. Through proteomic analysis of the MSI2-interacting RBP network and functional shRNA screening, we identified 24 genes required for in vivo leukemia. Syncrip was the most differentially required gene between normal and myeloid leukemia cells. SYNCRIP depletion increased apoptosis and differentiation while delaying leukemogenesis...
April 24, 2017: Nature Genetics
https://www.readbyqxmd.com/read/28429049/dysregulation-of-haematopoietic-stem-cell-regulatory-programs-in-acute-myeloid-leukaemia
#4
REVIEW
Silvia Basilico, Berthold Göttgens
Haematopoietic stem cells (HSC) are situated at the apex of the haematopoietic differentiation hierarchy, ensuring the life-long supply of mature haematopoietic cells and forming a reservoir to replenish the haematopoietic system in case of emergency such as acute blood loss. To maintain a balanced production of all mature lineages and at the same time secure a stem cell reservoir, intricate regulatory programs have evolved to control multi-lineage differentiation and self-renewal in haematopoietic stem and progenitor cells (HSPCs)...
April 20, 2017: Journal of Molecular Medicine: Official Organ of the "Gesellschaft Deutscher Naturforscher und Ärzte"
https://www.readbyqxmd.com/read/28428443/mechanisms-of-pinometostat-epz-5676-treatment-emergent-resistance-in-mll-rearranged-leukemia
#5
Carly T Campbell, Jessica N Haladyna, David A Drubin, Ty M Thomson, Michael J Maria, Taylor Yamauchi, Nigel J Waters, Edward J Olhava, Roy M Pollock, Jesse J Smith, Robert A Copeland, Stephen J Blakemore, Kathrin M Bernt, Scott R Daigle
DOT1L is a protein methyltransferase involved in the development and maintenance of MLL-rearranged (MLL-r) leukemia through its ectopic methylation of histones associated with well characterized leukemic genes.  Pinometostat (EPZ-5676), a selective inhibitor of DOT1L, is in clinical development in relapsed/refractory acute leukemia patients harboring rearrangements of the MLL gene. The observation of responses and subsequent relapses in the adult trial treating MLL-r patients motivated preclinical investigations into potential mechanisms of pinometostat treatment emergent resistance (TER) in cell lines confirmed to have MLL-r...
April 20, 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/28425697/conserved-helix-flanking-prolines-modulate-intrinsically-disordered-protein-target-affinity-by-altering-the-lifetime-of-the-bound-complex
#6
Michael D Crabtree, Wade Borcherds, Anusha Poosapati, Sarah L Shammas, Gary W Daughdrill, Jane Clarke
Appropriate integration of cellular signals requires a delicate balance of ligand-target binding affinities. Increasing the level of residual structure in intrinsically disordered proteins (IDPs), which are overrepresented in these cellular processes, has been shown previously to enhance binding affinities and alter cellular function. Conserved proline residues are commonly found flanking regions of IDPs that become helical upon interacting with a partner protein. Here, we mutate these helix-flanking prolines in p53 and MLL and find opposite effects on binding affinity upon an increase in free IDP helicity...
April 26, 2017: Biochemistry
https://www.readbyqxmd.com/read/28415763/low-numbers-of-pre-leukemic-fusion-genes-are-frequently-present-in-umbilical-cord-blood-without-affecting-dna-damage-response
#7
Pavol Kosik, Milan Skorvaga, Matus Durdik, Lukas Jakl, Ekaterina Nikitina, Eva Markova, Katarina Kozics, Eva Horvathova, Igor Belyaev
Despite widely accepted notion that many childhood leukemias are likely developed from hematopoietic stem/progenitor cells (HSPC) with pre-leukemic fusion genes (PFG) formed in embryonic/fetal development, the data on PFG incidence in newborns are contradictive. To provide a better understanding of a prenatal origin of leukemia, umbilical cord blood from 500 newborns was screened for the presence of the most frequent PFG associated with pediatric B-cell acute lymphoblastic leukemia. This screening revealed relatively high incidence of ETV6-RUNX1, BCR-ABL1 (p190) and MLL-AF4 at very low frequencies, averaging ~14 copies per 100,000 cells...
March 15, 2017: Oncotarget
https://www.readbyqxmd.com/read/28412727/znf521-sustains-the-differentiation-block-in-mll-rearranged-acute-myeloid-leukemia
#8
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...
February 16, 2017: Oncotarget
https://www.readbyqxmd.com/read/28412363/wdr5-positively-regulates-p53-stability-by-inhibiting-p53-ubiquitination
#9
Qingqing Xie, Zengpeng Li, Jianming Chen
WD40 repeat protein WDR5 is a core component of the Set/MLL histone methyltransferase complex which catalyzes histone H3 Lys4 trimethylation and activates gene transcription in human cells. WDR5 promotes Set/MLL complex assembly and mediates the complex binding to Lys4-dimethylated histone H3 tail. Most earlier studies report that WDR5 exerts profound effects on various cellular and organismal processes mainly through epigenetic regulation of gene transcription. However, the functions of WDR5 in lung cancer remain largely unknown...
April 12, 2017: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/28411381/pbx3-is-essential-for-leukemia-stem-cell-maintenance-in-mll-rearranged-leukemia
#10
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/28409790/mode-locked-laser-with-pulse-interleavers-in-a-monolithic-photonic-integrated-circuit-for-millimeter-wave-and-terahertz-carrier-generation
#11
Mu-Chieh Lo, Robinson Guzmán, Carlos Gordón, Guillermo Carpintero
This Letter presents a photonics-based millimeter wave and terahertz frequency synthesizer using a monolithic InP photonic integrated circuit composed of a mode-locked laser (MLL) and two pulse interleaver stages to multiply the repetition rate frequency. The MLL is a multiple colliding pulse MLL producing an 80 GHz repetition rate pulse train. Through two consecutive monolithic pulse interleaver structures, each doubling the repetition rate, we demonstrate the achievement of 160 and 320 GHz. The fabrication was done on a multi-project wafer run of a generic InP photonic technology platform...
April 15, 2017: Optics Letters
https://www.readbyqxmd.com/read/28408741/establishment-of-a-novel-human-lymphoblastic-cell-strain-with-the-long-arm-of-chromosome-11-aberration-without-mll-rearrangement
#12
Qian Wang, Lin Zhuang, Pei Li, Qiang Niu, Ping Zhu, Miao-Xia He, Hui Jiang, Chang-Cheng Liu, Min-Jun Wang, Li Chen, Hui Cheng, Yan Ma, Xiao-Xia Hu, Yi-Ping Hu, Xiao-Ping Xu
At present, all cell strains derived from acute lymphoblastic leukemia (ALL) patients with the long arm of chromosome 11 aberration are accompanied with mixed lineage leukemia (MLL) gene rearrangement. In this study, we established a permanent ALL cell strain CHH-1 with the long arm of chromosome 11 aberration and without MLL rearrangement, hoping that it could be used for the research of ALL with such genetic abnormality. CHH-1 cell strain was certified through morphology, immunophenotype, genetics and immunoglobulin (Ig) gene rearrangement analysis...
April 13, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28401483/molecular-profiling-of-gene-copy-number-abnormalities-in-key-regulatory-genes-in-high-risk-b-lineage-acute-lymphoblastic-leukemia-frequency-and-their-association-with-clinicopathological-findings-in-indian-patients
#13
Prerana Bhandari, Firoz Ahmad, Bibhu Ranjan Das
Genes related to key cellular pathways are frequently altered in B cell ALL and are associated with poor survival especially in high-risk (HR) subgroups. We examined gene copy number abnormalities (CNA) in 101 Indian HR B cell ALL patients and their correlation with clinicopathological features by multiplex ligation-dependent probe amplification. Overall, CNA were detected in 59 (59%) cases, with 26, 10 and 23% of cases harboring 1, 2 or +3 CNA. CNA were more prevalent in BCR-ABL1 (60%), pediatric (64%) and high WCC (WBC count) (63%) patients...
May 2017: Medical Oncology
https://www.readbyqxmd.com/read/28394257/cooperative-gene-activation-by-af4-and-dot1l-drives-mll-rearranged-leukemia
#14
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...
April 10, 2017: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/28379447/wdr5-in-porcine-preimplantation-embryos-expression-regulation-of-epigenetic-modifications-and-requirement-for-early-development1
#15
Biao Ding, Zubing Cao, Renyun Hong, Hui Li, Xiaoyuan Zuo, Lei Luo, Yunsheng Li, Weiping Huang, Wenyong Li, Kun Zhang, Yunhai Zhang
WDR5, a member of conserved WD40 protein family, is an essential component of the mixed lineage leukemia (MLL) complexes, which are crucial for numerous key biological processes including methylation of histone H3 lysine 4 (H3K4), self-renewal of embryonic stem cells, and formation of induced pluripotent stem cells. The expression pattern and functional role of WDR5 during porcine preimplantation embryonic development, however, remain unknown. Our results showed that the transcripts and protein of WDR5 exhibited stage-specific expression pattern in porcine early embryos...
March 31, 2017: Biology of Reproduction
https://www.readbyqxmd.com/read/28333413/extramedullary-leukemia-in-children-with-acute-myeloid-leukemia-a-population-based-cohort-study-from-the-nordic-society-of-pediatric-hematology-and-oncology-nopho
#16
Heidi Kristine Støve, Julie Damgaard Sandahl, Jonas Abrahamsson, Peter H Asdahl, Erik Forestier, Shau-Yin Ha, Kirsi Jahnukainen, Ólafur G Jónsson, Birgitte Lausen, Josefine Palle, Bernward Zeller, Henrik Hasle
BACKGROUND: The prognostic significance of extramedullary leukemia (EML) in childhood acute myeloid leukemia is not clarified. PROCEDURE: This population-based study included 315 children from the NOPHO-AML 2004 trial. RESULTS: At diagnosis, 73 (23%) patients had EML: 39 (12%) had myeloid sarcoma, 22 (7%) had central nervous system disease, and 12 (4%) had both. EML was associated with young age (median age: 2.6 years), a high white blood cell count (median: 40 × 10(9) /l), M5 morphology (40%), and 11q23/MLL (KMT2A) rearrangements (34%)...
March 23, 2017: Pediatric Blood & Cancer
https://www.readbyqxmd.com/read/28332877/pentraxin-3-as-a-new-cardiovascular-marker-in-adrenal-adenomas
#17
Muhammed Kizilgul, Selvihan Beysel, Ozgur Ozcelik, Seyfullah Kan, Mahmut Apaydin, Mustafa Caliskan, Bekir Ucan, Erkam Sencar, Seyda Ozdemir, Erman Cakal
BACKGROUND: Pentraxin 3 (PTX3) is an acute-phase glycoprotein, which is increased in patients with cardiovascular disease (CVD) and considered as a predictor of CVD in the general population. Both functional and nonfunctional adrenal tumors are associated with a higher risk of cardiovascular events and mortality. We aimed to investigate plasma PTX3 levels in patients with functioning and nonfunctioning adrenal tumors and to determine its relationship with cardiovascular risk factors. MATERIAL AND METHODS: Twenty-one patients with functional adrenal tumors (11 pheochromocytomas, 9 Cushing's Syndrome and 1 primary hyperaldosteronism), 28 patients with non-functional adrenal incidentilomas, and 40 healthy controls were enrolled in the study...
March 23, 2017: Endocrine Practice
https://www.readbyqxmd.com/read/28332262/haploidentical-peripheral-blood-stem-cell-transplantation-without-irradiation-or-busulfan-after-reduced-intensity-conditioning-for-kmt2a-mll-rearranged-infant-b-cell-precursor-acute-lymphoblastic-leukemia-report-of-two-cases
#18
Ai Yoshimi, Keisuke Kato, Sho Hosaka, Ryoko Suzuki, Hiroko Fukushima, Tomohei Nakao, Chie Kobayashi, Takashi Fukushima, Kazutoshi Koike, Ryo Sumazaki, Masahiro Tsuchida
We present two infants with KMT2A(MLL)-gene-R-associated BCP-ALL, who received HLA haploidentical PBSCT after RIC. The patients developed ALL at age 6 months and 3 months, respectively. Case 1 underwent PBSCT at the second CR with detectable KMT2A-AFF1(MLL-AF4) fusion gene transcript at 11 months of age, and Case 2 at the first CR without KMT2A-MLLT1(MLL-ENL) fusion gene transcript at 8 months of age. Both patients received G-CSF-mobilized unmanipulated peripheral blood mononuclear cells from their HLA haploidentical mothers after administration of FLU, MEL, and ATG...
March 22, 2017: Pediatric Transplantation
https://www.readbyqxmd.com/read/28286501/antigen-loss-variants-catching-hold-of-escaping-foes
#19
Maulik Vyas, Rolf Müller, Elke Pogge von Strandmann
Since mid-1990s, the field of cancer immunotherapy has seen steady growth and selected immunotherapies are now a routine and preferred therapeutic option of certain malignancies. Both active and passive cancer immunotherapies exploit the fact that tumor cells express specific antigens on the cell surface, thereby mounting an immune response specifically against malignant cells. It is well established that cancer cells typically lose surface antigens following natural or therapy-induced selective pressure and these antigen-loss variants are often the population that causes therapy-resistant relapse...
2017: Frontiers in Immunology
https://www.readbyqxmd.com/read/28283481/inhibition-of-pol-i-transcription-treats-murine-and-human-aml-by-targeting-the-leukemia-initiating-cell-population
#20
Nadine Hein, Donald P Cameron, Katherine M Hannan, Nhu-Y N Nguyen, Chun Yew Fong, Jirawas Sornkom, Meaghan Wall, Megan Pavy, Carleen Cullinane, Jeannine Diesch, Jennifer R Devlin, Amee J George, Elaine Sanij, Jaclyn Quin, Gretchen Poortinga, Inge Verbrugge, Adele Baker, Denis Drygin, Simon J Harrison, James D Rozario, Jason A Powell, Stuart M Pitson, Johannes Zuber, Ricky W Johnstone, Mark A Dawson, Mark A Guthridge, Andrew Wei, Grant A McArthur, Richard B Pearson, Ross D Hannan
Despite the development of novel drugs, prospects for many patients with acute myeloid leukemia (AML) remain dismal. This study reveals that the selective inhibitor of RNA Polymerase I (Pol I) transcription, CX-5461, effectively treats aggressive AML, including MLL-driven AML, and outperforms standard chemotherapies. In addition to the previously characterized mechanism of action of CX-5461, the induction of p53-dependant apoptotic cell death, inhibition of Pol I transcription also demonstrates potent efficacy in p53null AML in vivo...
March 10, 2017: Blood
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