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https://www.readbyqxmd.com/read/30107177/cooperative-enhancer-activation-by-tlx1-and-stat5-drives-development-of-nup214-abl1-tlx1-positive-t-cell-acute-lymphoblastic-leukemia
#1
Marlies Vanden Bempt, Sofie Demeyer, Michaël Broux, Jolien De Bie, Simon Bornschein, Nicole Mentens, Roel Vandepoel, Ellen Geerdens, Enrico Radaelli, Beat C Bornhauser, Andreas E Kulozik, Jules P Meijerink, Jean-Pierre Bourquin, Charles E de Bock, Jan Cools
The NUP214-ABL1 fusion is a constitutively activated tyrosine kinase that is significantly associated with overexpression of the TLX1 and TLX3 transcription factors in T cell acute lymphoblastic leukemia (T-ALL). Here we show that NUP214-ABL1 cooperates with TLX1 in driving T-ALL development using a transgenic mouse model and human T-ALL cells. Using integrated ChIP-sequencing, ATAC-sequencing, and RNA-sequencing data, we demonstrate that TLX1 and STAT5, the downstream effector of NUP214-ABL1, co-bind poised enhancer regions, and cooperatively activate the expression of key proto-oncogenes such as MYC and BCL2...
August 13, 2018: Cancer Cell
https://www.readbyqxmd.com/read/30106137/gene-regulatory-network-construction-identified-nfya-as-a-diffuse-subtype-specific-prognostic-factor-in-gastric-cancer
#2
Bin Cao, Yu Zhao, Zheng Zhang, Hengcun Li, Jie Xing, Shuilong Guo, Xintao Qiu, Shutian Zhang, Li Min, Shengtao Zhu
Lauren classification is a pathology-based gastric cancer (GC) subtyping system, which is widely used in the clinical treatment of patients with GC. However, genome-scale molecular characteristics to distinguish between diffuse (DF) and intestinal (IT) GC remain incompletely characterized, particularly at the transcriptional regulatory level. In the present study, gene regulatory networks were constructed using the Passing Attributes between Networks for Data Assimilation (PANDA) algorithm for DF, IT and mixed GC...
August 9, 2018: International Journal of Oncology
https://www.readbyqxmd.com/read/30104977/spinacetin-suppresses-the-mast-cell-activation-and-passive-cutaneous-anaphylaxis-in-mouse-model
#3
Ning Ji, Shunli Pan, Chen Shao, Yufen Chen, Zhe Zhang, Ran Wang, Yuling Qiu, Meihua Jin, Dexin Kong
We previously reported the anti-inflammatory and anti-asthmatic activities of the extract of the Inula japonica Thunb. Aiming for discovery of a novel anti-inflammatory compound, we isolated spinacetin from the extract and investigated its in vitro and in vivo anti-inflammatory effect and the related mechanism. Effect of spinacetin on the Syk signaling pathway was studied in bone marrow-derived mast cells (BMMCs), and that on the nuclear factor-κB (NF-κB) and mitogen-activated protein kinases (MAPKs) was investigated in Rat basophilic leukemia (RBL)-2H3 cells and human mast cell line (HMC-1)...
2018: Frontiers in Pharmacology
https://www.readbyqxmd.com/read/30104252/cd19-alterations-emerging-after-cd19-directed-immunotherapy-cause-retention-of-the-misfolded-protein-in-the-endoplasmic-reticulum
#4
Asen Bagashev, Elena Sotillo, Chih-Hang Anthony Tang, Kathryn L Black, Jessica Perazzelli, Steven H Seeholzer, Yair Argon, David M Barrett, Stephan A Grupp, Chih-Chi Andrew Hu, Andrei Thomas-Tikhonenko
We have previously described a mechanism of acquired resistance of B-cell acute lymphoblastic leukemia to CD19-directed chimeric antigen receptor T-cell (CART) immunotherapy. It was based on in-frame insertions in or skipping of CD19 exon 2. To distinguish between epitope loss and defects in surface localization, we used retroviral transduction and genome editing to generate cell lines expressing CD19 exon 2 variants (CD19ex2vs) bearing VSV-G tags. These lines were negative by live-cell flow cytometry with an anti-VSV-G antibody and resistant to killing by VSV-G directed antibody-drug conjugates (ADC), suggestive of a defect in surface localization...
August 13, 2018: Molecular and Cellular Biology
https://www.readbyqxmd.com/read/30104242/activation-of-th1-immunity-within-the-tumor-microenvironment-is-associated-with-clinical-response-to-lenalidomide-in-chronic-lymphocytic-leukemia
#5
Georg Aue, Clare Sun, Delong Liu, Jae-Hyun Park, Stefania Pittaluga, Xin Tian, Elinor Lee, Susan Soto, Janet Valdez, Irina Maric, Maryalice Stetler-Stevenson, Constance Yuan, Yusuke Nakamura, Pawel Muranski, Adrian Wiestner
Immune stimulation contributes to lenalidomide's antitumor activity. Chronic lymphocytic leukemia (CLL) is characterized by the accumulation of mature, autoreactive B cells in secondary lymphoid tissues, blood, and bone marrow and progressive immune dysfunction. Previous studies in CLL indicated that lenalidomide can repair defective T cell function in vitro. Whether T cell activation is required for clinical response to lenalidomide remains unclear. In this study, we report changes in the immune microenvironment in patients with CLL treated with single-agent lenalidomide and associate the immunologic effects of lenalidomide with antitumor response...
August 13, 2018: Journal of Immunology: Official Journal of the American Association of Immunologists
https://www.readbyqxmd.com/read/30104217/north-american-atll-has-a-distinct-mutational-and-transcriptional-profile-and-responds-to-epigenetic-therapies
#6
Urvi A Shah, Elaine Y Chung, Orsolya Giricz, Kith Pradhan, Keisuke Kataoka, Shanisha Gordon-Mitchell, Tushar D Bhagat, Yun Mai, Yongqiang Wei, Elise Ishida, Gaurav S Choudhary, Ancy Joseph, Ronald Rice, Nadege Gitego, Crystall Parrish, Matthias Bartenstein, Swati Goel, Ioannis Mantzaris, Aditi Shastri, Olga Derman, Adam Binder, Kira Gritsman, Noah Kornblum, Ira Braunschweig, Chirag Bhagat, Jeff Hall, Armin Graber, Lee Ratner, Yanhua Wang, Seishi Ogawa, Amit Verma, B Hilda Ye, Murali Janakiram
Adult T cell leukemia lymphoma (ATLL) is a rare T cell neoplasm, endemic in the Japanese, Caribbean and Latin American populations. Most North American ATLL patients are of Caribbean descent and are characterized by high rates of chemo-refractory disease and worse prognosis compared to the Japanese ATLL. To determine genomic differences between these two cohorts, we performed targeted exon sequencing on 30 North American ATLL patients and compared the results to the Japanese ATLL cases. Although the frequency of TP53 mutations was comparable, the mutation frequency in epigenetic and histone modifying genes (57%) was significantly higher whereas the mutation frequency in JAK/STAT and TCR/NF-κB pathway genes was significantly lower in our cohort...
August 13, 2018: Blood
https://www.readbyqxmd.com/read/30104084/a-case-of-subacute-combined-degeneration-of-the-spinal-cord-due-to-folic-acid-and-copper-deficiency
#7
Takuji Nakamura, Masanori Nishi, Mihoko Rikitake, Daisuke Koga, Junya Eto, Daisuke Tajima, Shuji Toda, Muneaki Matsuo
Subacute combined degeneration of the spinal cord (SACD) is a rare neurologic disorder manifesting progressive symptoms of paresthesia and spastic paralysis. Herein we present an autopsy case of SACD caused by folic acid and copper deficiency. A 16-year-old male presented with gradually worsening unsteady gait, and bladder and rectal dysfunction. He had a medical history of T-cell acute lymphoblastic leukemia (T-ALL), diagnosed 1.5 years previously. The patient had undergone chemotherapy, including methotrexate, as well as allogeneic bone mallow transplantation...
August 10, 2018: Brain & Development
https://www.readbyqxmd.com/read/30103821/foxp3-knockdown-inhibits-the-proliferation-and-reduces-notch1-expression-of-t-cell-acute-lymphoblastic-leukemia-cells
#8
Satoru Yonekura, Mai Itoh, Erika Shiratori, Mika Ohtaka, Shuji Tohda
OBJECTIVE: Forkhead box P3 (FOXP3) is a master transcriptional factor of regulatory T-cells (Tregs). Recent studies have shown that FOXP3 is associated with growth inhibition of cancer cells. However, the role of FOXP3 in acute T-lymphoblastic leukemia (T-ALL) cells is not known. It was also reported that NOTCH signaling promoted the expression of FOXP3 in Tregs. However, the effect of FOXP3 on NOTCH expression in T-ALL cells is little known. Therefore, we examined the effect of FOXP3 knockdown on the proliferation of T-ALL cells and NOTCH1 signaling...
August 13, 2018: BMC Research Notes
https://www.readbyqxmd.com/read/30097433/a-phase-i-iia-trial-using-cd19-targeted-third-generation-car-t-cells-for-lymphoma-and-leukemia
#9
Gunilla Enblad, Hannah Karlsson, Gustav Gammelgard, Jessica Wenthe, Tanja Lovgren, Rose-Marie Amini, Kristina I Wikstrom, Magnus Essand, Barbara Savoldo, Helene Hallbook, Martin Höglund, Gianpietro Dotti, Malcolm K Brenner, Hans Hagberg, Angelica Loskog
PURPOSE: CAR T cell therapy has been effective for patients with CD19+ B cell malignancies. Most studies have investigated second generation CARs with either CD28 or 4-1BB co-stimulatory domains in the CAR receptor. Here we describe the first clinical phase I/IIa trial using third generation CAR T cells targeting CD19 to evaluate safety and efficacy. EXPERIMENTAL DESIGN: Fifteen patients with B cell lymphoma or leukemia were treated with CAR T cells. The lymphoma patients received chemotherapy during CAR manufacture and eleven of fifteen were given low dose cyclophosphamide and fludarabine conditioning prior to CAR infusion...
August 10, 2018: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/30096712/generation-of-a-human-juvenile-myelomonocytic-leukemia-ipsc-line-chopi001-a-with-a-mutation-in-cbl
#10
Alyssa L Gagne, Jean Ann Maguire, Shilpa Gandre-Babbe, Stella T Chou, Sarah K Tasian, Mignon L Loh, Mitchell J Weiss, Paul Gadue, Deborah L French
Juvenile myelomonocytic leukemia (JMML) is a rare myeloproliferative disorder of early childhood characterized by expansion of clonal myelomonocytic cells and hyperactive Ras/MAPK signaling. The disorder is caused by somatic and/or germline mutations in genes involved in the Ras/MAPK and JAK/STAT signaling pathways, including CBL. Here we describe the generation of an iPSC line with a homozygous CBL c.1111T->C (Y371H) mutation, designated CHOPJMML1854.
July 5, 2018: Stem Cell Research
https://www.readbyqxmd.com/read/30094928/baseline-characteristics-and-outcomes-of-children-with-cancer-in-the-english-speaking-caribbean-a-multinational-retrospective-cohort
#11
T N Gibson, S Beeput, J Gaspard, C George, D Gibson, N Jackson, V Leandre-Broome, N Palmer-Mitchell, C Alexis, J Bird-Compton, C Bodkyn, R Boyle, S McLean-Salmon, M Reece-Mills, C Sin Quee-Brown, U Allen, S Weitzman, V Blanchette, S Gupta
BACKGROUND: English-speaking Caribbean (ESC) childhood cancer outcomes are unknown. PROCEDURE: Through the SickKids-Caribbean Initiative (SCI), we established a multicenter childhood cancer database across seven centers in six ESC countries. Data managers entered patient demographics, disease, treatment, and outcome data. Data collection commenced in 2013, with retrospective collection to 2011 and subsequent prospective collection. RESULTS: A total of 367 children were diagnosed between 2011 and 2015 with a median age of 5...
August 9, 2018: Pediatric Blood & Cancer
https://www.readbyqxmd.com/read/30093631/compatibility-of-runx1-eto-fusion-protein-modules-driving-cd34-human-progenitor-cell-expansion
#12
Linping Chen-Wichmann, Marina Shvartsman, Caro Preiss, Colin Hockings, Roland Windisch, Enric Redondo Monte, Georg Leubolt, Karsten Spiekermann, Jörn Lausen, Christian Brendel, Manuel Grez, Philipp A Greif, Christian Wichmann
Chromosomal translocations represent frequent events in leukemia. In t(8;21)+ acute myeloid leukemia, RUNX1 is fused to nearly the entire ETO protein, which contains four conserved nervy homology regions, NHR1-4. Furthermore RUNX1/ETO interacts with ETO-homologous proteins via NHR2, thereby multiplying NHR domain contacts. As shown recently, RUNX1/ETO retains oncogenic activity upon either deletion of the NHR3 + 4 N-CoR/SMRT interaction domain or substitution of the NHR2 tetramer domain. Thus, we aimed to clarify the specificities of the NHR domains...
August 9, 2018: Oncogene
https://www.readbyqxmd.com/read/30093506/the-btk-inhibitor-arq-531-targets-ibrutinib-resistant-cll-and-richter-s-transformation
#13
Sean David Reiff, Rose Mantel, Lisa L Smith, Joseph T Greene, Elizabeth M Muhowski, Catherine A Fabian, Virginia M Goettl, Minh Tran, Bonnie Harrington, Kerry A Rogers, Farrukh T Awan, Kami Maddocks, Leslie Andritsos, Amy M Lehman, Deepa Sampath, Rosa Lapalombella, Sudharshan Eathiraj, Giovanni Abbadessa, Brian Schwartz, Amy Johnson, John C Byrd, Jennifer A Woyach
Targeted inhibition of Bruton's tyrosine kinase (BTK) with the irreversible inhibitor ibrutinib has improved outcomes for patients with hematologic malignancies, including chronic lymphocytic leukemia (CLL). Here we describe preclinical investigations of ARQ 531, a potent, reversible inhibitor of BTK with additional activity against Src family kinases and kinases related to ERK signaling. We hypothesized that targeting additional kinases would improve global inhibition of signaling pathways, producing more robust responses...
August 9, 2018: Cancer Discovery
https://www.readbyqxmd.com/read/30093397/the-homeobox-transcription-factor-hb9-induces-senescence-and-blocks-differentiation-in-hematopoietic-stem-and-progenitor-cells
#14
Deborah Ingenhag, Sven Reister, Franziska Auer, Sanil Bhatia, Sarah Wildenhain, Daniel Picard, Marc Remke, Jessica I Hoell, Andreas Kloetgen, Dennis Sohn, Reiner U Jänicke, Gesine Koegler, Arndt Borkhardt, Julia Hauer
The homeobox gene HLXB9 encodes for the transcription factor HB9, which is essential for pancreatic as well as motor neuronal development. Beside its physiologic expression pattern, aberrant HB9 expression has been observed in several neoplasias. Especially in infant translocation t(7;12) acute myeloid leukemia aberrant HB9 expression is the only known molecular hallmark and assumed to be a key factor in leukemic transformation. However, up to now only poor functional data exist addressing the oncogenic potential of HB9 or its influence on hematopoiesis...
August 9, 2018: Haematologica
https://www.readbyqxmd.com/read/30093396/asxl2-regulates-hematopoiesis-in-mice-and-its-deficiency-promotes-myeloid-expansion
#15
Vikas Madan, Lin Han, Norimichi Hattori, Weoi Woon Teoh, Anand Mayakonda, Qiao-Yang Sun, Ling-Wen Ding, Hazimah Binte Mohd Nordin, Su Lin Lim, Pavithra Shyamsunder, Pushkar Dakle, Janani Sundaresan, Ngan B Doan, Masashi Sanada, Aiko Sato-Otsubo, Manja Meggendorfer, Henry Yang, Jonathan W Said, Seishi Ogawa, Torsten Haferlach, Der-Cherng Liang, Lee-Yung Shih, Tsuyoshi Nakamaki, Q Tian Wang, H Phillip Koeffler
Chromosomal translocation t(8;21)(q22;q22) which leads to generation of oncogenic RUNX1-RUNX1T1 (AML1-ETO) fusion is observed in about 10% of acute myelogenous leukemia (AML). To uncover somatic mutations that cooperate with t(8;21)-driven leukemia, we performed whole and targeted exome sequencing of an Asian cohort at diagnosis and relapse. We identified high frequency of truncating alterations in ASXL2 along with recurrent mutations of KIT, TET2, MGA, FLT3, and DHX15 in this subtype of AML. To investigate in-depth the role of ASXL2 in normal hematopoiesis, we utilized a mouse model of ASXL2 deficiency...
August 9, 2018: Haematologica
https://www.readbyqxmd.com/read/30093325/cord-blood-derived-cytokine-induced-killer-cells-combined-with-blinatumomab-as-a-therapeutic-strategy-for-cd19-tumors
#16
Josée Golay, Simona Martinelli, Rachele Alzani, Sabrina Cribioli, Clara Albanese, Elisa Gotti, Bruna Pasini, Benedetta Mazzanti, Riccardo Saccardi, Alessandro Rambaldi, Martino Introna
BACKGROUND: Cytokine-induced killer cells (CIKs) are an advanced therapeutic medicinal product (ATMP) that has shown therapeutic activity in clinical trials but needs optimization. We developed a novel strategy using CIKs from banked cryopreserved cord blood units (CBUs) combined with bispecific antibody (BsAb) blinatumomab to treat CD19+ malignancies. METHODS: CB-CIKs were expanded in vitro and fully characterized in comparison with peripheral blood (PB)-derived CIKs...
August 6, 2018: Cytotherapy
https://www.readbyqxmd.com/read/30092310/zinc-chitosan-nanoparticles-induced-apoptosis-in-human-acute-t-lymphocyte-leukemia-through-activation-of-tumor-necrosis-factor-receptor-cd95-and-apoptosis-related-genes
#17
Kandasamy Saravanakumar, Elango Jeevithan, Ramachandran Chelliah, Kandasamy Kathiresan, Wu Wen-Hui, Deog-Hwan Oh, Myeong-Hyeon Wang
Chitosan (CS), a novel biomaterial is widely used as a drug nano-carrier for cancer treatment. Towards this aim, anticancer and antibacterial activities of CS-nanoparticles-linked zinc (Zn-CSNPs) were evaluated. Particle size of CSNPs lowered (113.09 nm) compared to Zn-CSNPs (160.7 nm). Both nanoparticles (CSNPs and Zn-CSNPs) were spherical in shape, polydispersive, homogenous, amorphous and uniform size. Fourier transforms infrared spectrophotometer (FTIR) and energy dispersive X-ray spectroscopy (EDX) analysis confirmed the different molecular arrangement of NPs and presence of Zn in Zn-CSNPs and CS in both NPs, respectively...
August 6, 2018: International Journal of Biological Macromolecules
https://www.readbyqxmd.com/read/30092288/janus-kinase-2-activation-mechanisms-revealed-by-analysis-of-suppressing-mutations
#18
Henrik M Hammarén, Anniina T Virtanen, Bobin George Abraham, Heidi Peussa, Stevan R Hubbard, Olli Silvennoinen
BACKGROUND: Janus kinases (JAK1-3, TYK2) mediate cytokine signals in the regulation of hematopoiesis and immunity. JAK2 clinical mutations cause myeloproliferative neoplasms and leukemia and the mutations strongly concentrate in the regulatory pseudokinase domain, JAK homology 2, JH2. Current clinical JAK inhibitors target the tyrosine kinase domain and lack mutation- and pathway-selectivity. OBJECTIVE: To characterize mechanisms and differences for pathogenic and cytokine-induced JAK2 activation to enable design of novel selective JAK inhibitors...
August 6, 2018: Journal of Allergy and Clinical Immunology
https://www.readbyqxmd.com/read/30091222/bullous-cd4-cd8-adult-t-cell-leukemia-lymphoma-a-rare-diagnostically-challenging-cutaneous-variant
#19
Preetha D Kamath, Jennifer L Abrahams, Jeong Hee Cho-Vega
Human T-cell lymphotropic virus-1 (HTLV-1) is a retrovirus that causes adult T-cell leukemia/lymphoma (ATLL), an aggressive malignancy of CD4+ T-lymphocytes. This virus is endemic to the Caribbean, Japan, and regions of South America and Africa.[1] In Miami/ South Florida, whose population is enriched with immigrants from HTLV-1 endemic areas, we have identified multiple cases of ATLL. [2] This article is protected by copyright. All rights reserved.
August 9, 2018: Journal of Cutaneous Pathology
https://www.readbyqxmd.com/read/30089953/cytodiagnosis-of-coexistence-of-leukemic-infiltration-and-extramedullary-hematopoiesis-in-a-cervical-lymph-node-in-t-cell-leukemia-patient
#20
Akanksha Bothale, Kalpana Bothale, Sadhana Mahore, Trupti Dongre
Extramedullary hematopoiesis (EMH) is a compensatory mechanism that occurs when the marrow is unable to maintain sufficient red cell mass. EMH generally occurs in the patients with deficient bone marrow hematopoiesis secondary to either peripheral red cell destruction or marrow replacement. Although EMH is known to occur in agnogenic myeloid metaplasia with myelofibrosis, chronic myelogenous leukemia, thalassemia, and infiltrative disorders, such as lymphomas, it is rare in acute leukemias. EMH is most commonly seen in the liver and spleen as a diffuse lesion...
July 2018: Journal of Cytology
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