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https://www.readbyqxmd.com/read/28619982/jak1-2-and-bcl2-inhibitors-synergize-to-counteract-bone-marrow-stromal-cell-induced-protection-of-aml
#1
Riikka Karjalainen, Tea Pemovska, Mihaela Popa, Minxia Liu, Komal K Javarappa, Muntasir M Majumder, Bhagwan Yadav, David Tamborero, Jing Tang, Dmitrii Bychkov, Mika Kontro, Alun Parsons, Minna Suvela, Mireia Mayoral Safont, Kimmo Porkka, Tero Aittokallio, Olli Kallioniemi, Emmet McCormack, Bjørn T Gjertsen, Krister Wennerberg, Jonathan Knowles, Caroline A Heckman
The bone marrow (BM) provides a protective microenvironment to support the survival of leukemic cells and influence their response to therapeutic agents. In acute myeloid leukemia (AML), the high rate of relapse may in part be due to the inability of current treatment to effectively overcome the protective influence of the BM niche. To better understand the impact of the BM microenvironment on drug responses in AML, we conducted a comprehensive evaluation of 304 inhibitors, including approved and investigational agents, comparing ex vivo responses of primary AML cells in BM stroma-derived and standard culture conditions...
June 15, 2017: Blood
https://www.readbyqxmd.com/read/28614781/cell-lines-generated-from-a-chronic-lymphocytic-leukemia-mouse-model-exhibit-constitutive-btk-and-akt-signaling
#2
Simar Pal Singh, Saravanan Y Pillai, Marjolein J W de Bruijn, Ralph Stadhouders, Odilia B J Corneth, Henk Jan van den Ham, Alice Muggen, Wilfred van IJcken, Erik Slinger, Annemieke Kuil, Marcel Spaargaren, Arnon P Kater, Anton W Langerak, Rudi W Hendriks
Chronic lymphocytic leukemia (CLL) is characterized by the accumulation of mature CD5+ B cells in blood. Spontaneous apoptosis of CLL cells in vitro has hampered in-depth investigation of CLL pathogenesis. Here we describe the generation of three monoclonal mouse cell lines, EMC2, EMC4 and EMC6, from the IgH.TEμ CLL mouse model based on sporadic expression of SV40 large T antigen. The cell lines exhibit a stable CD5+CD43+IgM+CD19+ CLL phenotype in culture and can be adoptively transferred into Rag1-/- mice...
May 26, 2017: Oncotarget
https://www.readbyqxmd.com/read/28600336/diagnosis-and-classification-of-hematologic-malignancies-on-the-basis-of-genetics
#3
Justin Taylor, Wenbin Xiao, Omar Abdel-Wahab
Genomic analysis has greatly influenced the diagnosis and clinical management of patients affected by diverse forms of hematologic malignancies. Here we review how genetic alterations define subclasses of patients with acute leukemias, myelodysplastic syndromes (MDS), myeloproliferative neoplasms (MPNs), non-Hodgkin lymphomas and classical Hodgkin lymphoma. These include new subtypes of acute myeloid leukemia defined by mutations in RUNX1 or BCR-ABL1 translocations as well as a constellation of somatic structural DNA alterations in acute lymphoblastic leukemia...
June 9, 2017: Blood
https://www.readbyqxmd.com/read/28589551/centre-characteristics-and-procedure-related-factors-have-an-impact-on-outcomes-of-allogeneic-transplantation-for-patients-with-cll-a-retrospective-analysis-from-the-european-society-for-blood-and-marrow-transplantation-ebmt
#4
Johannes Schetelig, Liesbeth C de Wreede, Niels S Andersen, Carol Moreno, Michel van Gelder, Antonin Vitek, Michal Karas, Mauricette Michallet, Maciej Machaczka, Martin Gramatzki, Dietrich Beelen, Jürgen Finke, Julio Delgado, Liisa Volin, Jakob Passweg, Peter Dreger, Nicolaas Schaap, Eva Wagner, Anja Henseler, Anja van Biezen, Martin Bornhäuser, Simona Iacobelli, Hein Putter, Stefan O Schönland, Nicolaus Kröger
The best approach for allogeneic haematopoietic stem cell transplantations (alloHCT) in patients with chronic lymphocytic leukaemia (CLL) is unknown. We therefore analysed the impact of procedure- and centre-related factors on 5-year event-free survival (EFS) in a large retrospective study. Data of 684 CLL patients who received a first alloHCT between 2000 and 2011 were analysed by multivariable Cox proportional hazards models with a frailty component to investigate unexplained centre heterogeneity. Five-year EFS of the whole cohort was 37% (95% confidence interval [CI], 34-42%)...
June 7, 2017: British Journal of Haematology
https://www.readbyqxmd.com/read/28586310/effective-control-of-acute-myeloid-leukaemia-and-acute-lymphoblastic-leukaemia-progression-by-telomerase-specific-adoptive-t-cell-therapy
#5
Sara Sandri, Francesco De Sanctis, Alessia Lamolinara, Federico Boschi, Ornella Poffe, Rosalinda Trovato, Alessandra Fiore, Sara Sartori, Andrea Sbarbati, Attilio Bondanza, Simone Cesaro, Mauro Krampera, Maria T Scupoli, Michael I Nishimura, Manuela Iezzi, Silvia Sartoris, Vincenzo Bronte, Stefano Ugel
Telomerase (TERT) is a ribonucleoprotein enzyme that preserves the molecular organization at the ends of eukaryotic chromosomes. Since TERT deregulation is a common step in leukaemia, treatments targeting telomerase might be useful for the therapy of hematologic malignancies. Despite a large spectrum of potential drugs, their bench-to-bedside translation is quite limited, with only a therapeutic vaccine in the clinic and a telomerase inhibitor at late stage of preclinical validation. We recently demonstrated that the adoptive transfer of T cell transduced with an HLA-A2-restricted T-cell receptor (TCR), which recognize human TERT with high avidity, controls human B-cell chronic lymphocytic leukaemia (B-CLL) progression without severe side-effects in humanized mice...
May 23, 2017: Oncotarget
https://www.readbyqxmd.com/read/28580304/significance-of-inactivated-genes-in-leukemia-pathogenesis-and-prognosis
#6
REVIEW
Nazanin Heidari, Saeid Abroun, Jessika Bertacchini, Tina Vosoughi, Fakher Rahim, Najmaldin Saki
Epigenetic and genetic alterations are two mechanisms participating in leukemia, which can inactivate genes involved in leukemia pathogenesis or progression. The purpose of this review was to introduce various inactivated genes and evaluate their possible role in leukemia pathogenesis and prognosis. By searching the mesh words "Gene, Silencing AND Leukemia" in PubMed website, relevant English articles dealt with human subjects as of 2000 were included in this study. Gene inactivation in leukemia is largely mediated by promoter's hypermethylation of gene involving in cellular functions such as cell cycle, apoptosis, and gene transcription...
2017: Cell Journal
https://www.readbyqxmd.com/read/28575699/a-novel-spliced-variant-of-the-tin2-shelterin-is-present-in-chronic-lymphocytic-leukemia
#7
Ganchimeg Ishdorj, Sara E F Kost, Sara Beiggi, Yunli Zang, Spencer B Gibson, James B Johnston
The shelterin proteins play important roles in telomere maintenance and genome stability. These proteins have been found to be mutated in many cancers including CLL. Herein, we demonstrate here the presence of a novel spliced isoform of TIN2S in chronic lymphocytic leukemia (CLL), related to deletion of exon 2 in the TIN2 gene. The expressions of spliced TIN2S mRNA varied widely in CLL and there was an inverse relationship between the mRNA levels of full-length TIN2S and the spliced moiety. Small amounts of spliced TIN2S were also observed in normal B cells but not in T cells...
May 29, 2017: Leukemia Research
https://www.readbyqxmd.com/read/28573905/regulatory-t-cells-drive-immune-dysfunction-in-cll
#8
Deepesh Lad, Romy Hoeppli, Qing Huang, Rosa Garcia, Lixin Xu, Cynthia Toze, Raewyn Broady, Megan Levings
No abstract text is available yet for this article.
June 2, 2017: Leukemia & Lymphoma
https://www.readbyqxmd.com/read/28566736/aberrant-splicing-of-the-tumor-suppressor-cyld-promotes-the-development-of-chronic-lymphocytic-leukemia-via-sustained-nf-%C3%AE%C2%BAb-signaling
#9
M Hahn, J-P Bürckert, C A Luttenberger, S Klebow, M Hess, M Al-Maarri, M Vogt, S Reißig, M Hallek, A Wienecke-Baldacchino, T Buch, C P Muller, C P Pallasch, F T Wunderlich, A Waisman, N Hövelmeyer
The pathogenesis of chronic lymphocytic leukemia (CLL) has been linked to constitutive NF-κB activation but the underlying mechanisms are poorly understood. Here we show that alternative splicing of the negative regulator of NF-κB and tumor suppressor gene CYLD regulates the pool of CD5(+) B-cells through sustained canonical NF-κB signaling. Reinforced canonical NF-κB activity leads to the development of B1 cell-associated tumor formation in aging mice by promoting survival and proliferation of CD5(+) B-cells, highly reminiscent of human B-CLL...
June 1, 2017: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
https://www.readbyqxmd.com/read/28557814/significance-of-frequencies-compositions-and-or-antileukemic-activity-of-dc-stimulated-invariant-nkt-nk-and-cik-cells-on-the-outcome-of-patients-with-aml-all-and-cll
#10
Corinna L Boeck, Daniel C Amberger, Fatemeh Doraneh-Gard, Wishnu Sutanto, Thomas Guenther, Joerg Schmohl, Friedhelm Schuster, Helmut Salih, Florian Babor, Arndt Borkhardt, Helga Schmetzer
Invariant natural killer T (iNKT)/natural killer (NK)/cytokine-induced killer (CIK) cells are important for immune surveillance. (I) Novel combinations of antibody 6B11 (targeting the Vα24-Jα18-invariant T-cell receptor) with CD4/CD8/CD1d/Vα24 for iNKT subset detection and "T/NK cell-like"-iNKT subsets were defined. Compared with healthy peripheral blood mononuclear cells (MNC) (significantly) lower proportions of iNKT cells (6B11/6B11CD3/6B11CD161), NK cells (CD3CD56/CD3CD161), and CIK cells (CD3CD56/CD3CD161) were found in peripheral blood MNC from acute myeloid (AML)/acute myeloid, lymphoid (ALL)/chronic lymphoid leukemia (CLL) patients in acute disease stages...
July 2017: Journal of Immunotherapy
https://www.readbyqxmd.com/read/28556989/weight-based-dosing-of-alemtuzumab-an-ounce-of-prevention
#11
Joshua J Augustine
Alemtuzumab is a lymphocyte-depleting humanized monoclonal antibody that targets CD52 and binds to T and B lymphocytes, macrophages, monocytes and natural killer cells.(1) It was approved decades ago for the treatment of B-cell chronic lymphocytic leukemia (CLL), and the use of alemtuzumab in kidney transplantation was first described in the late 1990s as a drug that could promote tolerance and allow for maintenance drug minimization.(2) Although there has been variability in dosing in renal transplantation(3-5) , alemtuzumab is typically administered at a dosage of 30 mg intravenously once or twice in the perioperative transplant period, which is a fraction the cumulative dosage used for CLL...
May 30, 2017: Transplant International: Official Journal of the European Society for Organ Transplantation
https://www.readbyqxmd.com/read/28523450/a-review-of-the-clinical-pharmacokinetics-pharmacodynamics-and-immunogenicity-of-vedolizumab
#12
REVIEW
Maria Rosario, Nathanael L Dirks, Catherine Milch, Asit Parikh, Michael Bargfrede, Tim Wyant, Eric Fedyk, Irving Fox
Vedolizumab is a humanized anti-α4β7 integrin monoclonal antibody that selectively blocks trafficking of memory T cells to inflamed gut tissue by inhibiting the α4β7-mucosal addressin cell adhesion molecule-1 (MAdCAM-1) interaction. Approved for treating patients with moderately to severely active ulcerative colitis (UC) or Crohn's disease (CD), vedolizumab is administered as a 300 mg intravenous infusion. Vedolizumab undergoes a rapid, saturable, non-linear, target-mediated elimination process at low concentrations and a slower, linear, non-specific elimination process at higher concentrations...
May 18, 2017: Clinical Pharmacokinetics
https://www.readbyqxmd.com/read/28512625/using-murine-models-to-investigate-tumor-lymphoid-interactions-spotlight-on-chronic-lymphocytic-leukemia-and-angioimmunoblastic-t-cell-lymphoma
#13
REVIEW
Tyler A Herek, Christine E Cutucache
The role of the tumor microenvironment in leukemias and lymphomas is well established, yet the intricacies of how the malignant cells regulate and influence their non-malignant counterparts remain elusive. For example, chronic lymphocytic leukemia (CLL) is an expansion of malignant CD5(+)CD19(+) B cells, yet the non-malignant T cells play just as large of a role in disease presentation and etiology. Herein, we review the dynamic tumor cell to lymphoid repertoire interactions found in two non-Hodgkin's lymphoma subtypes: CLL and angioimmunoblastic T-cell lymphoma...
2017: Frontiers in Oncology
https://www.readbyqxmd.com/read/28468797/selective-inhibition-of-nuclear-export-with-selinexor-in-patients-with-non-hodgkin-s-lymphoma
#14
John Kuruvilla, Michael Savona, Rachid Baz, Morten Mau-Sorensen, Nashat Gabrail, Ramiro Garzon, Richard Stone, Michael Wang, Lynn Savoie, Peter Martin, Ian Flinn, Meagan Jacoby, T J Unger, Jean R Saint-Martin, Tami Rashal, Sharon Friedlander, Robert Carlson, Michael Kauffman, Sharon Shacham, Martin Gutierrez
Patients with relapsed or refractory (R/R) non-Hodgkin's lymphoma (NHL) have a poor prognosis and limited treatment options. We evaluated selinexor, an orally bioavailable, first-in-class inhibitor of the nuclear export protein XPO1, in this phase 1 trial to assess safety and determine a recommended phase 2 dose (RP2D). Seventy-nine patients with various NHL histologies, including diffuse large B cell lymphoma (DLBCL), Richter's transformation, mantle cell lymphoma (MCL), follicular lymphoma (FL) and chronic lymphocytic leukemia (CLL) were enrolled...
May 3, 2017: Blood
https://www.readbyqxmd.com/read/28465529/wnt5a-induces-ror1-to-complex-with-hs1-to-enhance-migration-of-chronic-lymphocytic-leukemia-cells
#15
K Hasan, J Yu, L Chen, B Cui, G F Widhopf, L Rassenti, Z Shen, S P Briggs, T J Kipps
ROR1 is a conserved, oncoembryonic surface-antigen expressed in chronic lymphocytic leukemia (CLL). We found that ROR1 associates with Hematopoietic-lineage-cell-Specific protein 1 (HS1) in freshly-isolated CLL cells or in CLL cells cultured with exogenous Wnt5a. Wnt5a also induced HS1 tyrosine phosphorylation, recruitment of ARHGEF1, activation of RhoA, and enhanced chemokine-directed migration; such effects could be inhibited by cirmtuzumab, a humanized anti-ROR1 mAb. We generated truncated forms of ROR1 and found its extra-cellular cysteine-rich domain or kringle domain was necessary for Wnt5a-induced HS1 phosphorylation...
May 3, 2017: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
https://www.readbyqxmd.com/read/28465528/wnt5a-induces-ror1-to-associate-with-14-3-3%C3%AE-for-enhanced-chemotaxis-and-proliferation-of-chronic-lymphocytic-leukemia-cells
#16
J Yu, L Chen, Y Chen, K Hasan, E M Ghia, L Zhang, R Wu, L Z Rassenti, G F Widhopf, Z Shen, S P Briggs, T J Kipps
Wnt5a can activate Rho GTPases in chronic lymphocytic leukemia cells by inducing the recruitment of ARHGEF2 to ROR1. Mass spectrometry on immune-precipitates of Wnt5a-activated ROR1 identified 14-3-3ζ, which was confirmed by co-immunoprecipitation. The capacity of Wnt5a to induce ROR1 to complex with 14-3-3ζ could be blocked in CLL cells treated with cirmtuzumab, a humanized mAb targeting ROR1. Silencing 14-3-3ζ via siRNA impaired the capacity of Wnt5a to: (1) induce recruitment of ARHGEF2 to ROR1, (2) enhance in vitro exchange activity of ARHGEF2, and (3) induce activation of RhoA and Rac1 in CLL cells...
May 3, 2017: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
https://www.readbyqxmd.com/read/28465341/invariant-nkt-cells-contribute-to-chronic-lymphocytic-leukemia-surveillance-and-prognosis
#17
Francesca Gorini, Laura Azzimonti, Gloria Delfanti, Lydia Scarfò, Cristina Scielzo, Maria Teresa Bertilaccio, Pamela Ranghetti, Alessandro Gulino, Claudio Doglioni, Arianna Di Napoli, Miriam Capri, Claudio Franceschi, Federico Caligaris-Cappio, Paolo Ghia, Matteo Bellone, Paolo Dellabona, Giulia Casorati, Claudia de Lalla
Chronic lymphocytic leukemia (CLL) is characterized by the expansion of malignant CD5(+) B lymphocytes in blood, bone marrow and lymphoid organs. CD1d-restricted invariant Natural Killer T (iNKT) cells are innate-like T lymphocytes strongly implicated in tumor surveillance. We investigated the impact of iNKT cells in the natural history of the disease both in Eμ;-Tcl1 (Tcl1) CLL mouse model and 68 CLL patients. We found that Tcl1-CLL cells express CD1d and iNKT cells critically delay the disease onset, but become functionally impaired upon disease progression...
May 2, 2017: Blood
https://www.readbyqxmd.com/read/28424162/pembrolizumab-in-patients-with-chronic-lymphocytic-leukemia-with-richter-s-transformation-and-relapsed-cll
#18
Wei Ding, Betsy R LaPlant, Timothy G Call, Sameer A Parikh, Jose F Leis, Rong He, Tait D Shanafelt, Sutapa Sinha, Jennifer Le-Rademacher, Andrew L Feldman, Thomas M Habermann, Thomas E Witzig, Gregory A Wiseman, Yi Lin, Erik Asmus, Grzegorz S Nowakowski, Michael J Conte, Deborah A Bowen, Casey N Aitken, Daniel L Van Dyke, Patricia T Greipp, Xin Liu, Xiaosheng Wu, Henan Zhang, Charla R Secreto, Shulan Tian, Esteban Braggio, Linda E Wellik, Ivana Micallef, David S Viswanatha, Huihuang Yan, Asher A Chanan-Khan, Neil E Kay, Haidong Dong, Stephen M Ansell
CLL patients progressed early on ibrutinib often develop Richter's transformation (RT) with short survival about 4 months. Preclinical studies suggest that programmed death 1 (PD-1) pathway is critical to inhibit immune surveillance in CLL. This phase 2 study MC1485 (NCT02332980) was designed to test the efficacy and safety of pembrolizumab, a humanized PD-1-blocking antibody, at a dose of 200 mg every 3 weeks in relapsed and transformed CLL. Twenty-five patients including 16 relapsed CLL and 9 RT (all proven diffuse large cell lymphoma) patients were enrolled and 60% received prior ibrutinib...
April 19, 2017: Blood
https://www.readbyqxmd.com/read/28423121/telomere-length-analysis-in-monoclonal-b-cell-lymphocytosis-and-chronic-lymphocytic-leukemia-binet-a
#19
F M Furtado, P S Scheucher, B A Santana, N F Scatena, R T Calado, E M Rego, D M Matos, R P Falcão
Monoclonal B-cell lymphocytosis (MBL) is an asymptomatic clinical entity characterized by the proliferation of monoclonal B cells not meeting the diagnosis criteria for chronic lymphocytic leukemia (CLL). MBL may precede the development of CLL, but the molecular mechanisms responsible for disease progression and evolution are not completely known. Telomeres are usually short in CLL and their attrition may contribute to disease evolution. Here, we determined the telomere lengths of CD5+CD19+ cells in MBL, CLL, and healthy volunteers...
April 13, 2017: Brazilian Journal of Medical and Biological Research, Revista Brasileira de Pesquisas Médicas e Biológicas
https://www.readbyqxmd.com/read/28416773/changes-in-t-cell-subpopulations-and-cytokine-network-during-early-period-of-ibrutinib-therapy-in-chronic-lymphocytic-leukemia-patients-the-significant-decrease-in-t-regulatory-cells-number
#20
Monika Podhorecka, Aneta Goracy, Agnieszka Szymczyk, Malgorzata Kowal, Blanca Ibanez, Olga Jankowska-Lecka, Arkadiusz Macheta, Aleksandra Nowaczynska, Elzbieta Drab-Urbanek, Sylwia Chocholska, Dariusz Jawniak, Marek Hus
B cell receptor (BCR) stimulation signal plays an important role in the pathogenesis of chronic lymphocytic leukemia (CLL), and kinase inhibitors directed toward the BCR pathway are now the promising anti-leukemic drugs. Ibrutinib, a Bruton tyrosine kinase inhibitor, demonstrates promising clinical activity in CLL. It is reported that ibrutinib, additionally to directly targeting leukemic cells, also inhibits the interactions of these cells with T cells, macrophages and accessory cells. Assessment of these mechanisms is important because of their non -direct anti-leukemic effects and to identify possible side effects connected with long-term drug administration...
May 23, 2017: Oncotarget
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