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https://www.readbyqxmd.com/read/28102226/chronic-lymphocytic-leukaemia
#1
Thomas J Kipps, Freda K Stevenson, Catherine J Wu, Carlo M Croce, Graham Packham, William G Wierda, Susan O'Brien, John Gribben, Kanti Rai
Chronic lymphocytic leukaemia (CLL) is a malignancy of CD5(+) B cells that is characterized by the accumulation of small, mature-appearing lymphocytes in the blood, marrow and lymphoid tissues. Signalling via surface immunoglobulin, which constitutes the major part of the B cell receptor, and several genetic alterations play a part in CLL pathogenesis, in addition to interactions between CLL cells and other cell types, such as stromal cells, T cells and nurse-like cells in the lymph nodes. The clinical progression of CLL is heterogeneous and ranges from patients who require treatment soon after diagnosis to others who do not require therapy for many years, if at all...
January 19, 2017: Nature Reviews. Disease Primers
https://www.readbyqxmd.com/read/28096407/development-of-chronic-allergic-responses-by-dampening-bcl6-mediated-suppressor-activity-in-memory-t-helper-2-cells
#2
Takashi Ogasawara, Masahiko Hatano, Hisae Satake, Jun Ikari, Toshibumi Taniguchi, Nobuhide Tsuruoka, Haruko Watanabe-Takano, Lisa Fujimura, Akemi Sakamoto, Hirokuni Hirata, Kumiya Sugiyama, Yasutsugu Fukushima, Susumu Nakae, Kenji Matsumoto, Hirohisa Saito, Takeshi Fukuda, Kazuhiro Kurasawa, Koichiro Tatsumi, Takeshi Tokuhisa, Masafumi Arima
Mice deficient in the transcriptional repressor B-cell CLL/lymphoma 6 (Bcl6) exhibit similar T helper 2 (TH2) immune responses as patients with allergic diseases. However, the molecular mechanisms underlying Bcl6-directed regulation of TH2 cytokine genes remain unclear. We identified multiple Bcl6/STAT binding sites (BSs) in TH2 cytokine gene loci. We found that Bcl6 is modestly associated with the BSs, and it had no significant effect on cytokine production in newly differentiated TH2 cells. Contrarily, in memory TH2 (mTH2) cells derived from adaptively transferred TH2 effectors, Bcl6 outcompeted STAT5 for binding to TH2 cytokine gene loci, particularly Interleukin4 (Il4) loci, and attenuated GATA binding protein 3 (GATA3) binding to highly conserved intron enhancer regions in mTH2 cells...
January 17, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28077600/ibrutinib-therapy-increases-t-cell-repertoire-diversity-in-patients-with-chronic-lymphocytic-leukemia
#3
Qingsong Yin, Mariela Sivina, Harlan Robins, Erik Yusko, Marissa Vignali, Susan O'Brien, Michael J Keating, Alessandra Ferrajoli, Zeev Estrov, Nitin Jain, William G Wierda, Jan A Burger
The Bruton's tyrosine kinase inhibitor ibrutinib is a highly effective, new targeted therapy for chronic lymphocytic leukemia (CLL) that thwarts leukemia cell survival, growth, and tissue homing. The effects of ibrutinib treatment on the T cell compartment, which is clonally expanded and thought to support the growth of malignant B cells in CLL, are not fully characterized. Using next-generation sequencing technology, we characterized the diversity of TCRβ-chains in peripheral blood T cells from 15 CLL patients before and after 1 y of ibrutinib therapy...
January 11, 2017: Journal of Immunology: Official Journal of the American Association of Immunologists
https://www.readbyqxmd.com/read/28074063/direct-in-vivo-evidence-for-increased-proliferation-of-cll-cells-in-lymph-nodes-compared-to-bone-marrow-and-peripheral-blood
#4
T M Herndon, S-S Chen, N S Saba, J Valdez, C Emson, M Gatmaitan, X Tian, T E Hughes, C Sun, D C Arthur, M Stetler-Stevenson, C M Yuan, C U Niemann, G E Marti, G Aue, S Soto, M Z H Farooqui, S E M Herman, N Chiorazzi, A Wiestner
Chronic Lymphocytic Leukemia (CLL) is a progressive malignancy of mature B-cells that involves the peripheral blood (PB), lymph nodes (LNs) and bone marrow (BM). While the majority of CLL cells are in a resting state, small populations of proliferating cells exist; however, the anatomical site of active cell proliferation remains to be definitively determined. Based on findings that CLL cells in LNs have increased expression of B-cell activation genes, we tested the hypothesis that the fraction of 'newly born' cells would be highest in the LNs...
January 11, 2017: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
https://www.readbyqxmd.com/read/28070536/establishment-a-cho-cell-line-expressing-human-cd52-molecule
#5
Tati Kadijeh, Yazdanpanah-Samani Mahsa, Ramezani Amin, Mahmoudi Maymand Elham, Ghaderi Abbas
BACKGROUND: CD52 is a small glycoprotein with a GPI anchor at its C-terminus. CD52 is expressed by Normal and malignant T and B lymphocytes and monocytes. There are detectable amounts of soluble CD52 in plasma of patients with CLL and could be used as a tumor marker. Although the biological function of CD52 is unknown but it seems that CD52 may be involved in migration and activation of T-cells .The aim of this study was to clone and express human CD52 gene in CHO cell line and studying its function in more details...
October 2016: Reports of Biochemistry & Molecular Biology
https://www.readbyqxmd.com/read/28067179/cd20-based-immunotherapy-of-b-cell-derived-hematologic-malignancies
#6
Dariush Shanehbandi, Jafar Majidi, Tohid Kazemi, Behzad Baradaran, Leili Aghebati-Maleki
CD20 is a surface antigen which is expressed at certain stages of B-cell differentiation. Targeting the CD20-positive B-cells with therapeutic monoclonal antibodies (MAbs) has been an effectual strategy in the treatment of hematologic malignancies such as non-Hodgkin's lymphoma (NHL) and chronic lymphocytic leukemia (CLL). Initial success with Rituximab (RTX) has encouraged the creation and development of more effective CD20 based therapeutics. However, treatment with conventional MAbs has not been adequate to overcome the problems such as refractory/relapsed disease...
January 9, 2017: Current Cancer Drug Targets
https://www.readbyqxmd.com/read/28038713/expression-of-lef1-in-mantle-cell-lymphoma
#7
Dennis P O'Malley, John P Lee, Andrew M Bellizzi
Small lymphocytic lymphoma/chronic lymphocytic leukemia (CLL/SLL) and mantle cell lymphoma (MCL) usually are distinctly different in regard to clinical presentation, morphology, immunophenotype and molecular/genetic findings. In spite of this, select cases may show overlapping characteristics and represent a diagnostic challenge. Recently LEF1 staining was identified as a fairly characteristic finding in CLL/SLL, with positivity identified in up to 95% of cases. LEF1 staining has not been reported as being present in cases of MCL, making this stain a useful tool in distinguishing these diagnoses...
February 2017: Annals of Diagnostic Pathology
https://www.readbyqxmd.com/read/28034907/comparison-of-acalabrutinib-a-selective-bruton-tyrosine-kinase-inhibitor-with-ibrutinib-in-chronic-lymphocytic-leukemia-cells
#8
Viralkumar Patel, Kumudha Balakrishnan, Elena Bibikova, Mary Ayres, Michael J Keating, William Wierda, Varsha Gandhi
PURPOSE: Ibrutinib inhibits Bruton tyrosine kinase (BTK) by irreversibly binding to the Cys-481 residue in the enzyme. However, ibrutinib also inhibits several other enzymes that contain cysteine residues homologous to Cys-481 in BTK. Patients with relapsed/refractory or previously untreated chronic lymphocytic leukemia (CLL) demonstrate a high overall response rate to ibrutinib with prolonged survival. Acalabrutinib, a selective BTK inhibitor designed to minimize off-target activity, has shown promising overall response rates in patients with relapsed/refractory CLL...
December 29, 2016: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28018857/murine-models-of-splenic-marginal-zone-lymphoma-a-role-for-cav1
#9
REVIEW
Chelsey L Patten, Christine E Cutucache
Dozens of murine models of indolent and aggressive B-cell lymphomas have been generated to date. These include those manifesting chronic lymphocytic leukemia (CLL), diffuse large B-cell lymphoma (DLBCL), as well as xenografts of mantle cell lymphoma (MCL). These models have led to an improved understanding of disease etiology, B-cell biology, immunomodulation, and the importance of the tumor microenvironment. Despite these efforts in CLL, DLBCL, and MCL, considerably little progress toward a model of splenic marginal zone lymphoma (SMZL) has been accomplished...
2016: Frontiers in Oncology
https://www.readbyqxmd.com/read/28017968/mutations-in-notch1-pest-domain-orchestrate-ccl19-driven-homing-of-chronic-lymphocytic-leukemia-cells-by-modulating-the-tumor-suppressor-gene-dusp22
#10
F Arruga, B Gizdic, C Bologna, S Cignetto, R Buonincontri, S Serra, T Vaisitti, K Gizzi, N Vitale, G Garaffo, E Mereu, F Diop, F Neri, D Incarnato, M Coscia, J Allan, R Piva, S Oliviero, R R Furman, D Rossi, G Gaidano, S Deaglio
Even if NOTCH1 is commonly mutated in Chronic Lymphocytic Leukemia (CLL), its functional impact in the disease remains unclear. Using CRISPR/Cas9-generated Mec-1 cell line models, we show that NOTCH1 regulates growth and homing of CLL cells by dictating expression levels of the tumor suppressor gene DUSP22. Specifically, NOTCH1 affects the methylation of DUSP22 promoter by modulating a nuclear complex, which tunes the activity of DNA methyltransferase 3A (DNMT3A). These effects are enhanced by PEST-domain mutations, which stabilize the molecule and prolong signaling...
December 26, 2016: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
https://www.readbyqxmd.com/read/28017967/duvelisib-treatment-is-associated-with-altered-expression-of-apoptotic-regulators-that-helps-in-sensitization-of-chronic-lymphocytic-leukemia-cells-to-venetoclax-abt-199
#11
V M Patel, K Balakrishnan, M Douglas, T Tibbitts, E Y Xu, J L Kutok, M Ayers, A Sarkar, R Guerrieri, W G Wierda, S O'Brien, N Jain, H M Stern, V Gandhi
Duvelisib, an oral dual inhibitor of PI3K-δ and PI3K-γ, is in phase III trials for the treatment of chronic lymphocytic leukemia (CLL) and indolent non-Hodgkin's lymphoma (iNHL). In CLL, duvelisib monotherapy is associated with high iwCLL and nodal response rates, but complete remissions are rare. To characterize the molecular effect of duvelisib, we obtained samples from CLL patients on the duvelisib phase I trial. Gene-expression studies (RNA seq, Nanostring, Affymetrix array, and real time RT-PCR) demonstrated increased expression of BCL2 along with several BH3-only pro-apoptotic genes...
December 26, 2016: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
https://www.readbyqxmd.com/read/28011996/the-kinase-inhibitors-r406-and-gs-9973-impair-t-cell-functions-and-macrophage-mediated-anti-tumor-activity-of-rituximab-in-chronic-lymphocytic-leukemia-patients
#12
Ana Colado, María Belén Almejún, Enrique Podaza, Denise Risnik, Carmen Stanganelli, Esteban Enrique Elías, Patricia Dos Santos, Irma Slavutsky, Horacio Fernández Grecco, María Cabrejo, Raimundo Fernando Bezares, Mirta Giordano, Romina Gamberale, Mercedes Borge
Small molecules targeting kinases involved in B cell receptor signaling are showing encouraging clinical activity in chronic lymphocytic leukemia (CLL) patients. Fostamatinib (R406) and entospletinib (GS-9973) are ATP-competitive inhibitors designed to target spleen tyrosine kinase (Syk) that have shown clinical activity with acceptable toxicity in trials with CLL patients. Preclinical studies with these inhibitors in CLL have focused on their effect in patient-derived leukemic B cells. In this work we show that clinically relevant doses of R406 and GS-9973 impaired the activation and proliferation of T cells from CLL patients...
December 23, 2016: Cancer Immunology, Immunotherapy: CII
https://www.readbyqxmd.com/read/27994839/romidepsin-controls-chronic-lymphocytic-leukemia-in-a-patient-with-mycosis-fungoides
#13
David M Lemchak, Oleg E Akilov
Romidepsin belongs to a class of medications called histone deacetylase inhibitors and is currently approved for treatment of cutaneous and peripheral T-cell lymphomas. Romidepsin was previously investigated for the treatment of chronic lymphocytic leukemia (CLL), and demonstrated potential benefit, but interest in its use declined following phase I clinical trials that showed poor tolerance of a significant side effect profile. We presented a patient with a history of stage II CLL, referred to dermatology for treatment of new-onset of mycosis fungoides (MF), who was treated with romidepsin over seven months...
November 2, 2016: Hematology Reports
https://www.readbyqxmd.com/read/27977057/randomized-phase-2-study-of-otlertuzumab-and-bendamustine-versus-bendamustine-in-patients-with-relapsed-chronic-lymphocytic-leukaemia
#14
Tadeusz Robak, Andrzej Hellmann, Janusz Kloczko, Javier Loscertales, Ewa Lech-Maranda, John M Pagel, Anthony Mato, John C Byrd, Farrukh T Awan, Holger Hebart, Jose A Garcia-Marco, Brian T Hill, Michael Hallek, Amy J Eisenfeld, Scott C Stromatt, Ulrich Jaeger
Otlertuzumab (TRU-016) is a humanized anti-CD37 protein therapeutic that triggers direct caspase-independent apoptosis of malignant B cells and induces antibody-dependent cell-mediated cytotoxicity. Patients with relapsed chronic lymphocytic leukaemia (CLL) received either otlertuzumab (20 mg/kg) weekly by IV infusion for two 28-day cycles then every 14 days for four 28-day cycles and IV bendamustine (70 mg/m(2) ) on Days 1 and 2 of each cycle for up to six 28-day cycles or bendamustine alone. Thirty-two patients were treated with otlertuzumab and bendamustine and 33 with bendamustine alone...
December 15, 2016: British Journal of Haematology
https://www.readbyqxmd.com/read/27941287/adoptive-immunotherapy-utilizing-anti-cd19-chimeric-antigen-receptor-t-cells-for-b-cell-malignancies
#15
Iekuni Oh, Yukiko Oh, Ken Ohmine
Genetically modified T-cells with forced expression of anti-CD19 chimeric antigen receptor (CD19 CAR) have demonstrated promising clinical results for relapsed and refractory B cell malignancies in early clinical trial settings. The first beneficial tumor regressions were identified among approximately half of CLL patients in 2011. Similarly, CD19 CAR T-cells achieved remissions in about 80% of aggressive B-cell lymphomas in 2012. Furthermore, in 2013 this cellular therapy showed an extremely high rate of efficacy against refractory CD19 positive acute lymphoid leukemia, which had been regarded as the most difficult to treat hematologic disease...
2016: [Rinshō Ketsueki] the Japanese Journal of Clinical Hematology
https://www.readbyqxmd.com/read/27933341/intragenic-variations-in-btla-gene-influence-mrna-expression-of-btla-gene-in-chronic-lymphocytic-leukemia-patients-and-confer-susceptibility-to-chronic-lymphocytic-leukemia
#16
Lidia Karabon, Anna Partyka, Monika Jasek, Ewa Lech-Maranda, Olga Grzybowska-Izydorczyk, Agnieszka Bojarska-Junak, Edyta Pawlak-Adamska, Anna Tomkiewicz, Tadeusz Robak, Jacek Rolinski, Irena Frydecka
The aim of this study was to determine the association between polymorphisms in gene encoding B- and T-lymphocyte attenuator (BTLA) and susceptibility to chronic lymphocytic leukemia (CLL) and their influence on mRNA expression of BTLA gene in T and B cells from CLL patients (pts.). The following BTLA single-nucleotide polymorphisms (SNPs): rs2705511, rs1982809, rs9288952, rs76844316, rs16859633, rs9288953, rs2705535, rs1844089, rs2705565, rs2633580 were genotyped with use of TaqMan probes in 321 CLL pts. and in 470 controls...
December 8, 2016: Archivum Immunologiae et Therapiae Experimentalis
https://www.readbyqxmd.com/read/27928896/genomic-data-integration-in-chronic-lymphocytic-leukemia
#17
Juan Luis Fernández-Martínez, Enrique J deAndrés-Galiana, Stephen T Sonis
BACKGROUND: B-cell Chronic Lymphocytic Leukemia (CLL) is a heterogeneous disease and the most common adult leukemia in western countries. IgVH mutational status distinguishes two major types of CLL, which were associated with different prognosis and survival. Sequencing identified NOTCH1 and SF3B1 as the two main recurrent mutations. We described a novel method to elucidate how these mutations affect gene expression by finding small-scale signatures to predict the IgVH, NOTCH1 and SF3B1 mutations...
December 8, 2016: Journal of Gene Medicine
https://www.readbyqxmd.com/read/27927767/t-cells-in-chronic-lymphocytic-leukemia-display-dysregulated-expression-of-immune-checkpoints-and-activation-markers
#18
Marzia Palma, Giusy Gentilcore, Kia Heimersson, Fariba Mozaffari, Barbro Näsman-Glaser, Emma Young, Richard Rosenquist, Lotta Hansson, Anders Österborg, Håkan Mellstedt
Chronic lymphocytic leukemia is characterized by impaired immune functions largely due to profound T cell defects. T cell functions also depend on co-signaling receptors, inhibitory or stimulatory, known as immune checkpoints, including cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) and programmed death-1 (PD-1). Here we analyzed the T cell phenotype focusing on immune checkpoints and activation markers in chronic lymphocytic leukemia patients (n=80) with different clinical characteristics and compared to healthy controls...
December 7, 2016: Haematologica
https://www.readbyqxmd.com/read/27908880/an-anti-cd3-anti-cll-1-bispecific-antibody-for-the-treatment-of-acute-myeloid-leukemia
#19
Steven R Leong, Siddharth Sukumaran, Maria Hristopoulos, Klara Totpal, Shannon Stainton, Elizabeth Lu, Alfred Wong, Lucinda Tam, Robert Newman, Brian R Vuillemenot, Diego Ellerman, Chen Gu, Mary Mathieu, Mark S Dennis, Allen Nguyen, Bing Zheng, Crystal Zhang, Genee Lee, Yu-Waye Chu, Rodney A Prell, Kedan Lin, Steven T Laing, Andrew G Polson
Acute myeloid leukemia (AML) is major unmet medical need. Most patients have poor long-term survival and treatment has not significantly changed in 40 years. Recently, bispecific antibodies that redirect the cytotoxic activity of effector T-cells by binding to CD3, the signaling component of the T-cell receptor, and a tumor target have shown clinical activity. Notably, blinatumomab is approved to treat relapsed/refractory acute lymphoid leukemia. Here we describe the design, discovery, pharmacological activity, pharmacokinetics, and safety of a CD3 T-cell-dependent bispecific (TDB) full-length human IgG1 therapeutic antibody targeting CLL-1 that could potentially be used in humans to treat AML...
December 1, 2016: Blood
https://www.readbyqxmd.com/read/27904140/restrictions-in-the-t-cell-repertoire-of-chronic-lymphocytic-leukemia-high-throughput-immunoprofiling-supports-selection-by-shared-antigenic-elements
#20
A Vardi, E Vlachonikola, M Karypidou, E Stalika, V Bikos, K Gemenetzi, C Maramis, A Siorenta, A Anagnostopoulos, S Pospisilova, N Maglaveras, I Chouvarda, K Stamatopoulos, A Hadzidimitriou
Immunoglobulin (IG) gene repertoire restrictions strongly support antigen selection in the pathogenesis of chronic lymphocytic leukemia (CLL). Given the emerging multifarious interactions between CLL and bystander T cells, we sought to determine whether antigen(s) are also selecting T cells in CLL. We performed a large-scale, next-generation sequencing (NGS) study of the T-cell repertoire, focusing on major stereotyped subsets representing CLL subgroups with undisputed antigenic drive, but also included patients carrying non-subset IG rearrangements to seek for T-cell immunogenetic signatures ubiquitous in CLL...
January 3, 2017: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
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