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Cll genetics

Arianna Bottoni, Lara Rizzotto, Tzung-Huei Lai, Chaomei Liu, Lisa L Smith, Rose Mantel, Sean Reiff, Dalia El-Gamal, Karilyn Larkin, Amy J Johnson, Rosa Lapalombella, Amy Lehman, William Plunkett, John C Byrd, James S Blachly, Jennifer A Woyach, Deepa Sampath
BTK is a critical mediator of survival in B cell neoplasms. While BTK inhibitors have transformed therapy in CLL, high genetic risk patients are at risk for relapse and have a poor prognosis. Identification of novel therapeutic strategies for this group of patients is an urgent unmet clinical need, and therapies that target BTK via alternative mechanisms may fill this niche. Herein, we identify a set of miRNAs that target BTK in primary CLL cells and show that the HDAC repressor complex is recruited to these miRNA promoters to silence their expression...
October 17, 2016: Blood
Emili Montserrat, Tycho Bauman, Julio Delgado
Medicine has been 'personalized' (i.e. centred in persons) since its foundation. Recently, however, the term 'personalized medicine' (or, better, 'precision medicine') has been introduced to define 'a form of medicine that uses information about a person's genes, proteins, and environment to prevent, diagnose, and treat disease'. This concept has gained momentum thanks to next-generation-sequencing (NGS) techniques that allow identification of molecular characteristics unique to the patient and to the tumour...
March 2016: Best Practice & Research. Clinical Haematology
M-W Jin, S-M Xu, Q An, P Wang
OBJECTIVE: Leukemia is the most common cancer of childhood, with AML, CML, ALL and CLL being the most common. Environmental and genetic factors have been studied extensively in children with childhood leukemia. Other factors, such as the prenatal parental use of controlled substances, have not been investigated to the same degree. We review what is currently known about environmental and parental factors and the occurrence of leukemia in children. MATERIALS AND METHODS: Electronic databases were searched for studies correlated pediatric leukemia with (1) ionizing radiation; (2) benzene; (3) parental drug use (4) parental alcohol use; (5) genetic factors...
September 2016: European Review for Medical and Pharmacological Sciences
Gilad Itchaki, Jennifer R Brown
Venetoclax (VEN, ABT-199/GDC-0199) is an orally bioavailable BH3-mimetic that specifically inhibits the anti-apoptotic B-cell lymphoma/leukemia 2 (BCL2) protein. Although BCL2 overexpression is not genetically driven in chronic lymphocytic leukemia (CLL), it is nearly universal and represents a highly important and prevalent mechanism of apoptosis evasion, making it an attractive therapeutic target. This review summarizes the role of BCL2 in CLL pathogenesis, the development path targeting its inhibition prior to VEN, and the preclinical and clinical data regarding the effectiveness and safety of VEN...
October 2016: Therapeutic Advances in Hematology
Larry Mansouri, Daniel Noerenberg, Emma Young, Elena Mylonas, Maysaa Abdulla, Mareike Frick, Fazila Asmar, Viktor Ljungström, Markus Schneider, Kenichi Yoshida, Aron Skaftason, Tatjana Pandzic, Blanca Gonzalez, Anna Tasidou, Nils Waldhueter, Alfredo Rivas-Delgado, Maria Angelopoulou, Marita Ziepert, Christopher Maximilian Arends, Lucile Couronné, Dido Lenze, Claudia D Baldus, Christian Bastard, Jessica Okosun, Jude Fitzgibbon, Bernd Dörken, Hans G Drexler, Damien Roos-Weil, Clemens A Schmitt, Helga Duverger Munch-Petersen, Thorsten Zenz, Martin-Leo Hansmann, Jonathan C Strefford, Gunilla Enblad, Olivier A Bernard, Elisabeth Ralfkiaer, Martin Erlanson, Penelope Korkolopoulou, Magnus Hultdin, Theodora Papadaki, Kirsten Grønbæk, Armando Lopez-Guillermo, Seishi Ogawa, Ralf Küppers, Kostas Stamatopoulos, Niki Stavroyianni, George Kanellis, Andreas Rosenwald, Elias Campo, Rose-Marie Amini, German Ott, Theodoros P Vassilakopoulos, Michael Hummel, Richard Rosenquist, Frederik Damm
We recently reported a truncating deletion in the NFKBIE gene, which encodes IκBϵ, a negative feedback regulator of NF-κB, in clinically aggressive chronic lymphocytic leukemia (CLL). Preliminary data indicate enrichment of NFKBIE aberrations in other lymphoid malignancies, hence we screened a large patient cohort (n=1460) diagnosed with different lymphoid neoplasms. While NFKBIE deletions were infrequent in follicular lymphoma, splenic marginal-zone lymphoma, and T-cell acute lymphoblastic leukemia (<2%), slightly higher frequencies were seen in diffuse large B-cell lymphoma, mantle cell lymphoma, and primary CNS lymphoma (3-4%)...
September 26, 2016: Blood
S Kasar, J R Brown
Sequencing studies have been instrumental in understanding the genetic basis of chronic lymphocytic leukemia (CLL). Our recent whole-genome sequencing study focusing on lower cytogenetic risk CLL demonstrated that CLL mutations can be attributed to 3 key mutational processes-2 types of activation induced-cytidine deaminase (AID) signatures and an aging signature-that operate at different times throughout CLL evolution.
July 2016: Molecular & Cellular Oncology
Eman Al Mussaed, Hani Osman, Ghaleb Elyamany
BACKGROUND: The simultaneous Occurrence of chronic lymphocytic leukemia (CLL) and acute myeloid leukemia (AML) has been rarely reported. Most of these cases have been occurring more frequently as a secondary event in patients receiving chemotherapeutic agents for CLL. CASE PRESENTATION: We describe a case of a 77-year-old man who presented with fatigue, pallor and lower limb pain and weakness. Initial laboratory studies showed Hb 7.7 g/dl, WBC 279.6 × 10(9)/1, PLT 143× 10(9)/1...
2016: BMC Cancer
Sotirios Sachanas, Gerassimos A Pangalis, Petros Karouzakis, Efstathios Koulieris, Maria Moschogiannis, Christina Kalpadakis, Xanthi Yiakoumis, Dimitra Rontogianni
Malakoplakia, a rare granulomatous disease of infectious etiology, is commonly observed in immunocompromised patients. Chronic lymphocytic leukemia (CLL) is characterized by profound immune dysregulation resulting in significant infection-related morbidity and mortality, and several drugs used in CLL treatment have a severe immunosuppressive effect. Ibrutinib, has become a new standard-of-care in patients with CLL, especially for those harboring unfavorable genetic characteristics such as 17 p deletion, with however, unknown long-term immunological consequences...
September 2016: Anticancer Research
Richard Rosenquist, Andreas Rosenwald, Ming-Qing Du, Gianluca Gaidano, Patricia Groenen, Andrew Wotherspoon, Paolo Ghia, Philippe Gaulard, Elias Campo, Kostas Stamatopoulos
Similar to the inherent clinical heterogeneity of most, if not all, lymphoma entities, the genetic landscape of these tumors is markedly complex in the majority of cases, with a rapidly growing list of recurrently mutated genes discovered in recent years by next-generation sequencing technology. Whilst a few genes have been implied to have diagnostic, prognostic and even predictive impact, most gene mutations still require rigorous validation in larger, preferably prospective patient series, to scrutinize their potential role in lymphoma diagnostics and patient management...
September 2016: Haematologica
Alison Yeomans, Elizabeth Lemm, Sarah Wilmore, Breeze E Cavell, Beatriz Valle-Argos, Sergey Krysov, Marina Sanchez Hidalgo, Elodie Leonard, Anne E Willis, Francesco Forconi, Freda K Stevenson, Andrew J Steele, Mark J Coldwell, Graham Packham
Increased mRNA translation drives carcinogenesis and is an attractive target for the development of new anti-cancer drugs. In this work, we investigated effects of phenethylisothiocyanate (PEITC), a phytochemical with chemopreventive and anti-cancer activity, on mRNA translation. PEITC rapidly inhibited global mRNA translation in human breast cancer-derived MCF7 cells and mouse embryonic fibroblasts (MEFs). In addition to the known inhibitory effects of PEITC on mTORC1 activity, we demonstrate that PEITC increased eIF2α phosphorylation...
August 27, 2016: Oncotarget
Maria Ciccone, George Adrian Calin
Chronic lymphocytic leukemia (CLL) is the most common leukemia among adult population in western country. In the last decade, several findings have substantially revolutionized the old concept that CLL is a disease originating from mature, not-dividing cell with indolent clinical course. Notably, next generation sequencing (NGS) have contributed to deepen the knowledge of the cellular networks that imply the onset and the progression of CLL. Among genetic aberrations that are recurrently observed in B-cells from patients with CLL, microRNA deregulation represented the first epigenetic mechanism that has been identified...
August 25, 2016: MicroRNA
Radhika Kandaswamy, Georgina P Sava, Helen E Speedy, Sílvia Beà, José I Martín-Subero, James B Studd, Gabriele Migliorini, Philip J Law, Xose S Puente, David Martín-García, Itziar Salaverria, Jesús Gutiérrez-Abril, Carlos López-Otín, Daniel Catovsky, James M Allan, Elías Campo, Richard S Houlston
Chronic lymphocytic leukemia (CLL) is an adult B cell malignancy. Genome-wide association studies show that variation at 15q15.1 influences CLL risk. We deciphered the causal variant at 15q15.1 and the mechanism by which it influences tumorigenesis. We imputed all possible genotypes across the locus and then mapped highly associated SNPs to areas of chromatin accessibility, evolutionary conservation, and transcription factor binding. SNP rs539846 C>A, the most highly associated variant (p = 1.42 × 10(-13), odds ratio = 1...
August 23, 2016: Cell Reports
Emili Montserrat, Peter Dreger
The treatment of patients with chronic lymphocytic leukemia (CLL) whose tumor presents the del(17p)/TP53 mutation is a major challenge. Treatment with chemo(immuno)therapy, immunomodulators, or the anti-CD52 monoclonal antibody alemtuzumab produces transient, unsatisfactory responses. Reduced-intensity-conditioning allotransplantation produces sustained progression-free survival and overall survival (40%-60% at 5 years), equivalent to the cure of the disease, even in cases with adverse biomarkers. Unfortunately, despite improvements in this procedure, the non-relapse mortality continues to be high (15%-30%), and only highly selected patients (young, physically fit, with treatment-sensitive disease, not heavily pretreated, and with a fully matched donor) may benefit from the intervention without incurring unacceptable treatment-related risks...
August 2016: Clinical Lymphoma, Myeloma & Leukemia
Lijian Yu, Haesook Kim, Siddha N Kasar, Parul Benien, Wei Du, Kevin Hoang, Andrew Aw, Bethany Tesar, Reina Improgo, Stacey Fernandes, Saranya Radhakrishnan, Josephine L Klitgaard, Charles Lee, Gad Getz, Sunita R Setlur, Jennifer R Brown
Purpose Chronic lymphocytic leukemia (CLL) with 17p deletion typically progresses quickly and is refractory to most conventional therapies. However, some del(17p) patients do not progress for years, suggesting that del(17p) is not the only driving event in CLL progression. We hypothesize that other concomitant genetic abnormalities underlie the clinical heterogeneity of del(17p) CLL. Experimental Design We profiled the somatic mutations and copy number alterations (CNA) in a large group of del(17p) CLL as well as wild type CLL and analyzed the genetic basis of their clinical heterogeneity...
August 8, 2016: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
M Kontro, A Kumar, M M Majumder, S Eldfors, A Parsons, T Pemovska, J Saarela, B Yadav, D Malani, Y Fløisand, M Höglund, K Remes, B T Gjertsen, O Kallioniemi, K Wennerberg, C A Heckman, K Porkka
Inhibitors of BCL-2 such as venetoclax (ABT-199) and navitoclax (ABT-263) are clinically explored in several cancer types, including acute myeloid leukemia (AML), to selectively induce apoptosis in cancer cells. To identify robust biomarkers for BCL-2 inhibitor sensitivity, we evaluated the ex vivo sensitivity of fresh leukemic cells from 73 diagnosed and relapsed/refractory AML patients, then comprehensively assessed if the responses correlated to specific mutations or gene expression signatures. Compared to samples from healthy donor controls (non-sensitive) and chronic lymphocytic leukemia (CLL) patients (highly-sensitive), AML samples exhibited variable responses to BCL-2 inhibition...
August 8, 2016: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
Larry Mansouri, Nikos Papakonstantinou, Stavroula Ntoufa, Kostas Stamatopoulos, Richard Rosenquist
The nuclear factor-κB (NF-κB) pathway is constitutively activated in chronic lymphocytic leukemia (CLL) patients, and hence plays a major role in disease development and evolution. In contrast to many other mature B-cell lymphomas, only a few recurrently mutated genes involved in canonical or non-canonical NF-κB activation have been identified in CLL (i.e. BIRC3, MYD88 and NFKBIE mutations) and often at a low frequency. On the other hand, CLL B cells seem 'addicted' to the tumor microenvironment for their survival and proliferation, which is primarily mediated by interaction through a number of cell surface receptors, e...
August 2016: Seminars in Cancer Biology
Nadia Mensali, Fan Ying, Vincent Oei Yi Sheng, Weiwen Yang, Even Walseng, Shraddha Kumari, Lars-Egil Fallang, Arne Kolstad, Wolfgang Uckert, Karl Johan Malmberg, Sébastien Wälchli, Johanna Olweus
T cells engineered to express chimeric antigen receptors (CARs) targeted to CD19 are effective in treatment of B-lymphoid malignancies. However, CARs recognize all CD19 positive (pos) cells, and durable responses are linked to profound depletion of normal B cells. Here, we designed a strategy to specifically target patient B cells by utilizing the fact that T-cell receptors (TCRs), in contrast to CARs, are restricted by HLA. Two TCRs recognizing a peptide from CD20 (SLFLGILSV) in the context of foreign HLA-A*02:01 (CD20p/HLA-A2) were expressed as 2A-bicistronic constructs...
May 2016: Oncoimmunology
Shuhua Yi, Zengjun Li, Dehui Zou, Gang An, Rui Cui, Shizhen Zhong, Heng Li, Wenjie Xiong, Chenwen Li, Weiwei Chen, Wei Liu, Rui Lv, Zhen Yu, Huijun Wang, Yan Xu, Keshu Zhou, Kun Ru, Jianxiang Wang, Tao Cheng, Lugui Qiu
PURPOSE: Chronic lymphocytic leukemia (CLL) is a heterogeneous disease with cytogenetic aberrations that are still considered the gold standard of prognostic factors. However, heterogeneity remains within each cytogenetic group, especially in patients with concomitant cytogenetic aberrations. METHODS: A panel of DNA probes was used to detect cytogenetic aberrations, including RB1/D13S25 at 13q14, ATM at 11q22, TP53 at 17p13, CEP12 and IGH translocation at 14q32, by fluorescence in situ hybridization...
July 28, 2016: Genetics in Medicine: Official Journal of the American College of Medical Genetics
Burak Uz, Ilhan Dolasik, Ozlem Ucer, Adile Ferda Dagli, Sercan Simsek
In the present report, a 73 years-old male patient who developed clear cell type renal cell carcinoma (RCC) 5 years after the diagnosis of chronic lymphocytic lymphoma (CLL) and plausible explanations for this association were discussed by the authors. The incidence of CLL and RCC occurring in the same patient is higher than that expected in the general population. Various explicative hypotheses of this concurrence include treatment-related development of a second malignancy, immunomodulatory mechanisms, viral aetiology, cytokine (interleukin 6) release from a tumor, and common genetic mutations...
2016: Leukemia Research Reports
Nadja Zaborsky, Franz Josef Gassner, Daniela Asslaber, Petra Reinthaler, Ursula Denk, Sabine Flenady, Josefina Piñón Hofbauer, Barbara Danner, Stefan Rebhandl, Andrea Harrer, Roland Geisberger, Richard Greil, Alexander Egle
Chronic lymphocytic leukemia develops within a complex network driven by genetic mutations and microenvironmental interactions. Among the latter a complex interplay with the immune system is established by the clone. Next to a proposed recruitment of support from T and myeloid cells, potential anti-CLL immune reactions need to be subverted.By using TCL1 mice as a CLL model, we show that TCR-Vβ7+ NK1.1+ T cells are overrepresented in this disease model and constitute a main subset of peripheral CD3+ cells with biased TCR usage, showing that these cells account for a major part for T cell skewing in TCL1 mice...
July 1, 2016: Oncotarget
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