45 results
Search Results
2. Integrating multiple immunogenetic data sources for feature extraction and mining somatic hypermutation patterns: the case of "towards analysis" in chronic lymphocytic leukaemia.
- Author
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Kavakiotis, Ioannis, Xochelli, Aliki, Agathangelidis, Andreas, Tsoumakas, Grigorios, Maglaveras, Nicos, Stamatopoulos, Kostas, Hadzidimitriou, Anastasia, Vlahavas, Ioannis, and Chouvarda, Ioanna
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CHRONIC lymphocytic leukemia ,DATA integration ,FEATURE extraction ,IMMUNOGLOBULINS ,B cells - Abstract
Background: Somatic Hypermutation (SHM) refers to the introduction of mutations within rearranged V(D)J genes, a process that increases the diversity of Immunoglobulins (IGs). The analysis of SHM has offered critical insight into the physiology and pathology of B cells, leading to strong prognostication markers for clinical outcome in chronic lymphocytic leukaemia (CLL), the most frequent adult B-cell malignancy. In this paper we present a methodology for integrating multiple immunogenetic and clinocobiological data sources in order to extract features and create high quality datasets for SHM analysis in IG receptors of CLL patients. This dataset is used as the basis for a higher level integration procedure, inspired form social choice theory. This is applied in the Towards Analysis, our attempt to investigate the potential ontogenetic transformation of genes belonging to specific stereotyped CLL subsets towards other genes or gene families, through SHM. Results: The data integration process, followed by feature extraction, resulted in the generation of a dataset containing information about mutations occurring through SHM. The Towards analysis performed on the integrated dataset applying voting techniques, revealed the distinct behaviour of subset #201 compared to other subsets, as regards SHM related movements among gene clans, both in allele-conserved and non-conserved gene areas. With respect to movement between genes, a high percentage movement towards pseudo genes was found in all CLL subsets. Conclusions: This data integration and feature extraction process can set the basis for exploratory analysis or a fully automated computational data mining approach on many as yet unanswered, clinically relevant biological questions. [ABSTRACT FROM AUTHOR]
- Published
- 2016
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3. The Mysterious Actor—γδ T Lymphocytes in Chronic Lymphocytic Leukaemia (CLL).
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Zarobkiewicz, Michał K. and Bojarska-Junak, Agnieszka A.
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CHRONIC leukemia ,LYMPHOCYTIC leukemia ,CHRONIC lymphocytic leukemia ,T cells ,B cells ,CYTOTOXIC T cells ,LEUKEMIA - Abstract
Chronic lymphocytic leukaemia (CLL) is the most common leukaemia among adults. It is the clonal expansion of B cells expressing CD19 and CD5. Despite significant progress in treatment, CLL is still incurable. γδ T cells comprise an important subset of the cytotoxic T cells. Although γδ T cells in CLL are dysfunctional, they still can possibly be used for immunotherapy. The current paper reviews our understanding of γδ T lymphocytes in CLL. [ABSTRACT FROM AUTHOR]
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- 2022
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4. B cells behaving badly.
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Shim, Youn K., Silver, Sharon R., Caporaso, Neil E., Marti, Gerald E., Middleton, Dannie C., Linet, Martha S., and Vogt, Robert F.
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B cells ,CARCINOGENESIS ,LYMPHOPROLIFERATIVE disorders ,CHRONIC lymphocytic leukemia ,CELLULAR immunity ,MONOCLONAL antibodies ,CELL-mediated lympholysis ,BIOMARKERS - Abstract
The pathogenesis of B-cell lymphoproliferative disorders in general and B-cell chronic lymphocytic leukaemia in particular appears to involve dysfunctional regulation of humoral and cellular immunity with the subsequent development of genetic aberrations in B cells. In theory, either component may arise de novo or may be influenced by environmental exposures including infectious agents, antigens, genotoxic chemicals, or radiation. As an intermediary within the exposure-disease continuum, monoclonal B-cell lymphocytosis may be a helpful biomarker for teasing out these various contributions to risk. This article introduces a series of papers that resulted from an International Workshop held in May 2007 entitled ‘Monoclonal B-cell Lymphocytosis and Chronic Lymphocytic Leukemia: Environmental and Genetic Risk Factors’. Research efforts, such as those described in this issue, should lead to improved interventions, more predictive biomarkers, more effective treatments, and a greater appreciation of how the immune system functions over the entire human lifespan. [ABSTRACT FROM AUTHOR]
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- 2007
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5. Adaptive and Innate Cytotoxic Effectors in Chronic Lymphocytic Leukaemia (CLL) Subjects with Stable Disease.
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Rubino, Valentina, Carriero, Flavia, Palatucci, Anna Teresa, Giovazzino, Angela, Leone, Stefania, Nicolella, Valerio, Calabrò, Martina, Montanaro, Rosangela, Brancaleone, Vincenzo, Pane, Fabrizio, Chiurazzi, Federico, Ruggiero, Giuseppina, and Terrazzano, Giuseppe
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B cells ,LYMPHOCYTIC leukemia ,CHRONIC leukemia ,CHRONIC lymphocytic leukemia ,CYTOTOXIC T cells ,HLA histocompatibility antigens - Abstract
Chronic lymphocytic leukaemia (CLL) is characterised by the expansion of a neoplastic mature B cell clone. CLL clinical outcome is very heterogeneous, with some subjects never requiring therapy and some showing an aggressive disease. Genetic and epigenetic alterations and pro-inflammatory microenvironment influence CLL progression and prognosis. The involvement of immune-mediated mechanisms in CLL control needs to be investigated. We analyse the activation profile of innate and adaptive cytotoxic immune effectors in a cohort of 26 CLL patients with stable disease, as key elements for immune-mediated control of cancer progression. We observed an increase in CD54 expression and interferon (IFN)-γ production by cytotoxic T cells (CTL). CTL ability to recognise tumour-targets depends on human leukocyte antigens (HLA)-class I expression. We observed a decreased expression of HLA-A and HLA-BC on B cells of CLL subjects, associated with a significant reduction in intracellular calnexin that is relevant for HLA surface expression. Natural killer (NK) cells and CTL from CLL subjects show an increased expression of the activating receptor KIR2DS2 and a reduction of 3DL1 and NKG2A inhibiting molecules. Therefore, an activation profile characterises CTL and NK cells of CLL subjects with stable disease. This profile is conceivable with the functional involvement of cytotoxic effectors in CLL control. [ABSTRACT FROM AUTHOR]
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- 2023
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6. T‐helper cell regulation of CD45 phosphatase activity by galectin‐1 and CD43 governs chronic lymphocytic leukaemia proliferation.
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Imbery, John F., Heinzelbecker, Julia, Jebsen, Jenny K., McGowan, Marc, Myklebust, Camilla, Bottini, Nunzio, Stanford, Stephanie M., Skånland, Sigrid S., Tveita, Anders, Tjønnfjord, Geir E., Munthe, Ludvig A., Szodoray, Peter, and Nakken, Britt
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LYMPHOCYTIC leukemia ,CHRONIC leukemia ,CELLULAR control mechanisms ,CD45 antigen ,ANTIGEN receptors - Abstract
Summary: Chronic lymphocytic leukaemia (CLL) is characterised by malignant mature‐like B cells. Supportive to CLL cell survival is chronic B‐cell receptor (BCR) signalling; however, emerging evidence demonstrates CLL cells proliferate in response to T‐helper (Th) cells in a CD40L‐dependent manner. We showed provision of Th stimulation via CD40L upregulated CD45 phosphatase activity and BCR signalling in non‐malignant B cells. Consequently, we hypothesised Th cell upregulation of CLL cell CD45 activity may be an important regulator of CLL BCR signalling and proliferation. Using patient‐derived CLL cells in a culture system with activated autologous Th cells, results revealed increases in both Th and CLL cell CD45 activity, which correlated with enhanced downstream antigen receptor signalling and proliferation. Concomitantly increased was the surface expression of Galectin‐1, a CD45 ligand, and CD43, a CLL immunophenotypic marker. Galectin‐1/CD43 double expression defined a proliferative CLL cell population with enhanced CD45 activity. Targeting either Galectin‐1 or CD43 using silencing, pharmacology, or monoclonal antibody strategies dampened CD45 activity and CLL cell proliferation. These results highlight a mechanism where activated Th cells drive CLL cell BCR signalling and proliferation via Galectin‐1 and CD43‐mediated regulation of CD45 activity, identifying modulation of CD45 phosphatase activity as a potential therapeutic target in CLL. [ABSTRACT FROM AUTHOR]
- Published
- 2022
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7. Expression Of The Bcl2 Gene In Chronic Lymphocytic Leukaemia Patients.
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Vucicevic, Ksenija, Jakovljevic, Vladimir, Sretenovic, Jasmina, Tosic, Natasa, Kostic, Tatjana, Glumac, Irena, Colovic, Milica, Colovic, Natasa, Pavlovic, Sonja, and Karan-Djurasevic, Teodora
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CHRONIC lymphocytic leukemia ,GENE expression in mammals ,LYMPHOCYTIC leukemia ,APOPTOSIS ,CHRONIC diseases ,B cells ,PATIENTS ,MAMMALS - Abstract
Copyright of Serbian Journal of Experimental & Clinical Research is the property of Sciendo and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)
- Published
- 2015
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8. Molecular pathogenesis of chronic lymphocytic leukaemia.
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Crassini, Kyle, Stevenson, William S., Mulligan, Stephen P., and Best, O. Giles
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IMMUNOGLOBULIN heavy chains ,B cells ,LYMPH nodes ,BONE marrow - Abstract
Summary: Chronic lymphocytic leukaemia (CLL) is characterised by the clonal expansion of mature, CD5 positive, B lymphocytes in the blood, marrow, lymph nodes and spleen. For the majority of patients, CLL follows an indolent clinical course, while a proportion of patients experience rapid disease progression. Despite the strong correlation between certain genetic defects and prognosis, there remains no single unifying pathogenic lesion in CLL. With recent advances in therapy it is increasingly important to stratify CLL patients according to risk. This has been highlighted by two recent studies, the first showing that immunoglobulin heavy chain mutational status predicts a durable response to frontline chemoimmunotherapy and the second showing that complex karyotype is a stronger predictor of poor response to ibrutinib and venetoclax therapy than TP53 deletion. In this review we discuss the molecular features of CLL and how technological advances can identify patient subsets and stratify them according to risk. [ABSTRACT FROM AUTHOR]
- Published
- 2019
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9. Bendamustine for patients with indolent B cell lymphoproliferative malignancies including chronic lymphocytic leukaemia – an updated meta‐analysis.
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Vidal, Liat, Gurion, Ronit, Shargian, Liat, Dreyling, Martin, and Gafter‐Gvili, Anat
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B cells ,META-analysis ,THERAPEUTICS ,DATA quality ,CONFIDENCE intervals - Abstract
Summary: The question of which chemotherapy induction provides the best results for indolent lymphoma patients is yet unanswered. Different regimens have been compared, none of which has been shown to improve overall survival. The use of bendamustine is growing. A number of trials evaluated its efficacy for patients with indolent B‐cell lymphoid neoplasms, including chronic lymphocytic leukaemia (CLL). To evaluate the efficacy of bendamustine in that population we performed a systematic review and meta‐analysis of 9 randomised controlled trials (2726 patients). Bendamustine was compared to fludarabine‐containing regimens, CVP (cyclophosphamide, vincristine, prednisolone), CHOP (CVP+ doxorubicin) and chlorambucil. Due to insufficient reported data, six of the nine trials were included in analysis of overall survival. Bendamustine was associated with a prolonged overall survival, (hazard ratio 0·79, 95% confidence interval 0·65–0·95). Data regarding quality of life was reported for two trials, therefore too scarce to pool. The risk of neutropenia was reduced with bendamustine treatment compared to other chemotherapy. Bendamustine induction is an efficacious option for patients with indolent lymphoma, and CLL. Maintenance therapy was not evaluated after bendamustine induction, and potentially there is an interaction between the two. Chemotherapy‐free approach was shown to be efficacious for patients with CLL, while toxicity with that approach is not negligible. [ABSTRACT FROM AUTHOR]
- Published
- 2019
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10. A tale of two antibodies: obinutuzumab versus rituximab.
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Freeman, Ciara L. and Sehn, Laurie H.
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LYMPHOMA treatment ,CHRONIC lymphocytic leukemia treatment ,B cells ,DRUG resistance ,RITUXIMAB ,BIOSIMILARS - Abstract
Summary: While rituximab has dramatically improved outcomes for patients with CD20
+ malignancies for two decades, responses are not universal and resistance can develop. Obinutuzumab was developed to potentiate activity and overcome resistance. Pre‐clinical data suggests obinutuzumab is superior to rituximab at effecting B cell depletion; however recent phase III clinical trial results have been mixed. The decision of which antibody to employ will probably be further complicated by the approval of a subcutaneous preparation of rituximab and several anti‐CD20 biosimilars. Clinicians are now challenged with deciding whether to switch to obinutuzumab in approved settings, accepting the potential for increased toxicity and probable increased cost. The benefit conferred by obinutuzumab over rituximab may be context‐specific and vary based on histological subtype and immune integrity. This comprehensive review will explore the preclinical differences, investigate the proposed pathogenesis of rituximab resistance, compare the employed dosing strategies and interrogate available clinical results to help inform practice. [ABSTRACT FROM AUTHOR]- Published
- 2018
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11. An update for Richter syndrome - new directions and developments.
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Eyre, Toby A. and Schuh, Anna
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RICHTER syndrome ,PROTEIN-tyrosine kinases ,B cells ,POSITRON emission tomography ,IMMUNOSUPPRESSION - Abstract
High-grade transformation of chronic lymphocytic leukaemia [Richter syndrome (RS)] is rare and represents a unique and uncommon clinical challenge. Clonally related diffuse large B cell type RS is a chemotherapy-resistant and devastating disease. Patients are typically elderly, immunosuppressed and present with a rapidly deteriorating performance status. Historical outcomes suggest a median overall survival of approximately 8 months. RS remains is an area of high unmet clinical need. The molecular profile and treatment needs of patients are likely to change over time with the advent of novel B cell receptor inhibitors, monoclonal antibodies and BH3 mimetics. Herein, we summarise what is known regarding the molecular drivers of RS and the existing clinical trial data, including the recently published CHOP- OR (cyclophosphamide, doxorubicin, vincristine, prednisolone and ofatumumab followed by ofatumumab maintenance in newly diagnosed RS) trial. We discuss novel agents in development with a focus on the second-generation Bruton tyrosine kinase inhibitor acalabrutinib, checkpoint inhibition and the potential role of precision medicine in future trials of RS. [ABSTRACT FROM AUTHOR]
- Published
- 2017
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12. Ibrutinib enhances the efficacy of ROR1 bispecific T cell engager mediated cytotoxicity in chronic lymphocytic leukaemia.
- Author
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Gohil, Satyen H., Evans, Rachel, Harasser, Micaela, El‐Kholy, Mohamed, Paredes‐Moscosso, Solange R., Della Peruta, Marco, and Nathwani, Amit C.
- Subjects
T cells ,T cell receptors ,PERFORINS ,B cells - Abstract
The article discusses the ibrutinib enhances the efficacy of ROR1 bispecific T cell engager mediated cytotoxicity in chronic lymphocytic leukaemia. Topics include how receptor tyrosine kinase-like orphan receptor 1 (ROR1) is an onco-fetal antigen expressed in a range of solid and haematological malignancies, including acute lymphoblastic leukaemia (ALL) and chronic lymphocytic leukaemia.
- Published
- 2019
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13. Ofatumumab capacity to deplete B cells from chronic lymphocytic leukaemia is affected by C4 complement exhaustion.
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Tempescul, Adrian, Bagacean, Cristina, Riou, Catherine, Bendaoud, Boutahar, Hillion, Sophie, Debant, Marjolaine, Buors, Caroline, Berthou, Christian, and Renaudineau, Yves
- Subjects
LYMPHOCYTIC leukemia ,MONOCLONAL antibodies ,CD20 antigen ,B cells ,LYMPHOCYTOSIS ,LEUKEMIA treatment - Abstract
The management of patients with chronic lymphocytic leukaemia ( CLL) has improved with the utilisation of ofatumumab as a novel anti- CD20 monoclonal antibody. However, as half of the patients fail to respond to the treatment, the aim of this study was to evaluate circulating CLL cell depletion and clinical response according to the context of complement activation and Fcγ RIIIA polymorphism in ten CLL patients with relapsed/refractory disease. At the end of the treatment, results indicated that circulating CD5
+ CD19+ CLL cell depletion was major (<0.01 × 109 /L) in 4 of 10 patients, partial (>50% decrease) in 4 of 10 patients and ineffective for the two other patients. No clinical modifications were observed following ofatumumab introduction. Ofatumumab administration leads to a rapid and important exhaustion of complement C4 levels in patients with initial lymphocytosis. C4 exhaustion was accelerated in a non-responder patient, and incomplete in two patients with partial circulating depletion. Moreover, delaying weekly to monthly ofatumumab injections improved CLL cell depletion in two patients. Fcγ RIIIA 158 polymorphism ( FF n = 6 and VF n = 4) was not associated with major and/or partial circulating CLL cell depletion. In conclusion, ofatumumab induces an important C4 exhaustion that needs to be taken into account when treating CLL patients with ofatumumab. [ABSTRACT FROM AUTHOR]- Published
- 2016
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14. Nature and nurture: a case of transcending haematological pre-malignancies in a pair of monozygotic twins adding possible clues on the pathogenesis of B-cell proliferations.
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Hansen, Marcus C., Nyvold, Charlotte G., Roug, Anne S., Kjeldsen, Eigil, Villesen, Palle, Nederby, Line, and Hokland, Peter
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B cells ,CELL proliferation ,POLYCYTHEMIA ,AMAUROSIS fugax ,JANUS kinases ,LYMPHOCYTOSIS ,WNT genes ,RUNX proteins ,DISEASES - Abstract
We describe a comprehensive molecular analysis of a pair of monozygotic twins, who came to our attention when one experienced amaurosis fugax and was diagnosed with JAK2+ polycythaemia vera. He (Twin A) was also found to have an asymptomatic B-cell chronic lymphocytic leukaemia (B-CLL). Although JAK2−, Twin B was subsequently shown to have a benign monoclonal B-cell lymphocytosis ( MBL). Flow cytometric and molecular analyses of the B-cell compartments revealed different immunoglobulin light and heavy chain usage in each twin. We hypothesized that whole exome sequencing could help delineating the pattern of germline B-cell disorder susceptibility and reveal somatic mutations potentially contributing to the differential patterns of pre-malignancy. Comparing bone marrow cells and T cells and employing in-house engineered integrative analysis, we found aberrations in Twin A consistent with a myeloid neoplasm, i.e. in TET2, RUNX1, PLCB1 and ELF4. Employing the method for detecting high-ranking variants by extensive annotation and relevance scoring, we also identified shared germline variants in genes of proteins interacting with B-cell receptor signalling mediators and the WNT-pathway, including IRF8, PTPRO, BCL9L, SIT1 and SIRPB1, all with possible implications in B-cell proliferation. Similar patterns of IGHV-gene usage to those demonstrated here have been observed in inherited acute lymphoblastic leukaemia. Collectively, these findings may help in facilitating identification of putative master gene(s) involved in B-cell proliferations in general and MBL and B- CLL in particular. [ABSTRACT FROM AUTHOR]
- Published
- 2015
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15. ZAP70 expression directly promotes chronic lymphocytic leukaemia cell adhesion to bone marrow stromal cells.
- Author
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Lafarge, Sandrine T., Li, Hongzhao, Pauls, Samantha D., Hou, Sen, Johnston, James B., Gibson, Spencer B., and Marshall, Aaron J.
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CHRONIC lymphocytic leukemia ,PROTEIN expression ,STROMAL cells ,B cells ,CELL adhesion - Abstract
The article presents a study on correlation of ZAP70 protein expression with the disease chronic lymphocytic leukemia (CLL). It states the analyses of ZAP70 expression in CLL cells and its role in altering B cells which further promotes stromal cell adhesion. It mentions that ZAP70 proteins can alter B cells by affecting its signaling pathways either by its kinase or adaptor functions.
- Published
- 2015
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16. The frequency of TP53 gene defects differs between chronic lymphocytic leukaemia subgroups harbouring distinct antigen receptors.
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Malcikova, Jitka, Stalika, Evangelia, Davis, Zadie, Plevova, Karla, Trbusek, Martin, Mansouri, Larry, Scarfò, Lydia, Baliakas, Panagiotis, Gardiner, Anne, Sutton, Lesley ‐ Ann, Francova, Hana Skuhrova, Agathangelidis, Andreas, Anagnostopoulos, Achilles, Tracy, Ian, Makris, Antonis, Smardova, Jana, Ghia, Paolo, Belessi, Chrysoula, Gonzalez, David, and Rosenquist, Richard
- Subjects
P53 protein ,CHRONIC lymphocytic leukemia ,ANTIGEN receptors ,B cells ,CHROMOSOME abnormalities - Abstract
The article discusses the research on the frequency of TP53 gene defects between chronic lymphocytic leukemia subgroups harbouring distinct antigen receptors. It states that chronic lymphocytic leukemia (CLL) B-cell receptor (BcR) stereotypes exhibit distinct profiles of genomic aberrations. It mentions that the BcR-mediated selection as possible mechanism for acquisition or selection of genomic aberrations in CLL.
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- 2014
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17. Leukaemic cells from chronic lymphocytic leukaemia patients undergo apoptosis following microtubule depolymerization and Lyn inhibition by nocodazole.
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Frezzato, Federica, Trimarco, Valentina, Martini, Veronica, Gattazzo, Cristina, Ave, Elisa, Visentin, Andrea, Cabrelle, Anna, Olivieri, Valeria, Zambello, Renato, Facco, Monica, Zonta, Francesca, Cristiani, Andrea, Brunati, Anna Maria, Moro, Stefano, Semenzato, Gianpietro, and Trentin, Livio
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CHRONIC lymphocytic leukemia ,B cells ,CANCER cells ,PHYSIOLOGICAL effects of adenosine triphosphate ,NUCLEOTIDES - Abstract
Functional abnormalities of chronic lymphocytic leukaemia ( CLL) cells may be related to the microtubular network of cell cytoskeleton; specifically tubulin involvement in cells after B-cell receptor engagement. As microtubule inhibitors could represent a therapeutic strategy for CLL, this study investigated the capability of nocodazole, a synthetic depolymerizing agent, to kill CLL leukaemic cells. We demonstrated that nocodazole was highly specific for the in vitro induction of apoptosis in leukaemic cells from 90 CLL patients, without affecting the viability of T-cells and/or mesenchymal stromal cells ( MSCs) recovered from the same patients. Nocodazole was observed to overcome the pro-survival signals provided by MSCs. Competing with ATP for the nucleotide-binding site, nocodazole has been observed to turn off the high basal tyrosine phosphorylation of leukaemic cells mediated by the Src-kinase Lyn. Considering that most anti-microtubule drugs have limited clinical use because of their strong toxic effects, the high selectivity of nocodazole for leukaemic cells in CLL and its capability to bypass microenvironmental pro-survival stimuli, suggests the use of this inhibitor for designing new therapeutic strategies in CLL treatment. [ABSTRACT FROM AUTHOR]
- Published
- 2014
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18. High-throughput sequencing for the identification of NOTCH1 mutations in early stage chronic lymphocytic leukaemia: biological and clinical implications.
- Author
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Lionetti, Marta, Fabris, Sonia, Cutrona, Giovanna, Agnelli, Luca, Ciardullo, Carmela, Matis, Serena, Ciceri, Gabriella, Colombo, Monica, Maura, Francesco, Mosca, Laura, Gentile, Massimo, Recchia, Anna G., Ilariucci, Fiorella, Musolino, Caterina, Molica, Stefano, Di Raimondo, Francesco, Cortelezzi, Agostino, Rossi, Davide, Gaidano, Gianluca, and Morabito, Fortunato
- Subjects
CHRONIC lymphocytic leukemia ,GENETIC mutation ,B cells ,LYMPHOCYTOSIS ,NUCLEOTIDE sequence - Abstract
NOTCH1 mutations have recently emerged as new genetic lesions significantly correlated with survival in chronic lymphocytic leukaemia ( CLL). We performed deep next generation sequencing of the NOTCH1 mutation hotspot in 384 cases at diagnosis, including 100 monoclonal B cell lymphocytosis ( MBL) and 284 Binet stage A CLL cases, enrolled in the Gruppo Italiano Studio Linfomi O- CLL1 multicentre trial. The NOTCH1 c.7541_7542del CT dinucleotide deletion was detected and confirmed by an extremely sensitive polymerase chain reaction-based approach in 11% of MBL and 13·4% of CLL patients. Remarkably, the NOTCH1 mutation was often observed at low clonal level, mainly in MBL patients. Sequential analyses in a fraction of cases showed that the NOTCH1 mutation generally does not occur during the disease course and that the mutational load in positive cases tends to be stable over time. NOTCH1-mutated cases, even at low clonal level, displayed a significant reduction in median progression-free survival, although NOTCH1 mutation lost its prognostic impact in a multivariate analysis including 11q and/or 17p deletion, IGHV mutational status, and MBL or CLL status. Our data highlight the importance of using highly sensitive methods to measure NOTCH1 mutations, in order to improve prognostic stratification and obtain useful information for potential therapeutic approaches. [ABSTRACT FROM AUTHOR]
- Published
- 2014
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19. Nurse-like cells show deregulated expression of genes involved in immunocompetence.
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Bhattacharya, Nupur, Diener, Susanne, Idler, Irina S., Rauen, Judith, Häbe, Sarah, Busch, Hauke, Habermann, Annett, Zenz, Thorsten, Döhner, Hartmut, Stilgenbauer, Stephan, and Mertens, Daniel
- Subjects
GENE expression ,CHRONIC lymphocytic leukemia ,B cells ,LYSOZYMES ,IMMUNODEFICIENCY ,GENETICS - Abstract
Summary [ABSTRACT FROM AUTHOR]
- Published
- 2011
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20. Biological evaluation of CpG stimulation of normal human B-cells: implications for B-cell biology and cytogenetic analysis of CLL B-cells.
- Author
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Xiaosheng Wu, Smoley, Stephanie A., Peterson, Mark A., Walters, Denise K., Arendt, Bonnie K., Nowakowski, Grzegorz S., Van Dyke, Daniel L., Kay, Neil E., and Jelinek, Diane F.
- Subjects
NUCLEOTIDES ,CHROMOSOMES ,B cells ,LYMPHOCYTIC leukemia ,HUMAN cytogenetics - Abstract
The article reports on the use of CpG oligodeoxynucleotides (CpG) in clinical laboratories as a mitogenic tool to reveal chromosomal abnormalities in malignant B-cells from chronic lymphocytic leukemia (CLL) patients . It reports on a study conducted to validate the role of CpG in revealing cytogenetic abnormalities in CLL B-cells. It also reports on a study conducted to validate whether CpG stimulated B-cells.
- Published
- 2011
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21. Dasatinib inhibits B cell receptor signalling in chronic lymphocytic leukaemia but novel combination approaches are required to overcome additional pro-survival microenvironmental signals.
- Author
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McCaig, Alison M., Cosimo, Emilio, Leach, Michael T., and Michie, Alison M.
- Subjects
B cells ,CHRONIC lymphocytic leukemia ,PROTEIN-tyrosine kinases ,PHOSPHORYLATION ,MESENCHYMAL stem cells ,FLUDARABINE ,CELL receptors - Abstract
As antigenic stimulation of the B cell antigen receptor (BCR) is key to chronic lymphocytic leukaemia (CLL) pathogenesis, targeting dysregulated kinases involved in BCR signalling is an attractive therapeutic approach. We studied the effects of the Src/c-Abl tyrosine kinase inhibitor dasatinib on BCR signal transduction in CLL cells. Treatment of CLL cells with 100 nmol/l dasatinib induced apoptosis by an average reduction in viability of 33·7% at 48 h, with dasatinib sensitivity correlating with inhibition of Syk phosphorylation. Dasatinib inhibited calcium flux, phosphatidylinositol-3-kinase and mitogen-activated protein kinase activation following BCR crosslinking, and blocked the Mcl-1-dependent increase in CLL cell survival on prolonged BCR stimulation. However, the pro-apoptotic effect of dasatinib was abrogated by stromal cell contact alone or in the presence of CD154 and interleukin (IL)-4 (CD154L/IL-4 system). Whilst dasatinib retained the ability to sensitize CLL cells in stromal co-culture to both fludarabine and chlorambucil, the addition of CD154 and IL-4 rendered cells resistant to these drug combinations. We demonstrate that the HSP90 inhibitor 17-DMAG exhibited synergy with dasatinib in vitro, and moreover, induced apoptosis of CLL cells in the CD154L/IL-4 system. Our data provide evidence that dasatinib would be most clinically effective in combination with agents able to target antigen-independent microenvironmental signals. [ABSTRACT FROM AUTHOR]
- Published
- 2011
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22. A variant of the LRP4 gene affects the risk of chronic lymphocytic leukaemia transformation to Richter syndrome.
- Author
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Rasi, Silvia, Spina, Valeria, Bruscaggin, Alessio, Vaisitti, Tiziana, Tripodo, Claudio, Forconi, Francesco, De Paoli, Lorenzo, Fangazio, Marco, Sozzi, Elisa, Cencini, Emanuele, Laurenti, Luca, Marasca, Roberto, Visco, Carlo, Xu-Monette, Zijun Y., Gattei, Valter, Young, Ken H., Malavasi, Fabio, Deaglio, Silvia, Gaidano, Gianluca, and Rossi, Davide
- Subjects
LYMPHOCYTIC leukemia ,LYMPHOMAS ,NUCLEOTIDES ,B cells ,BIOINFORMATICS ,PROGNOSIS ,CANCER risk factors - Abstract
Richter syndrome (RS) represents the transformation of chronic lymphocytic leukaemia (CLL) to aggressive lymphoma. Risk factors of CLL transformation to RS are only partly known. We explored the role of the host genetic background as a risk factor for RS occurrence. Forty-five single nucleotide polimorphisms (SNPs) known to be relevant for CLL prognosis were genotyped in a consecutive cohort of 331 CLL, of which 21 had transformed to RS. After correcting for multiple testing and adjusting for previously reported RS risk factors, the LRP4 rs2306029 TT variant genotype was the sole SNP independently associated with a higher risk of RS transformation (Hazard Ratio: 4·17; P = 0·001; q = 0·047). The enrichment of LRP4 TT genotype in RS was confirmed in an independent series ( n = 44) used for validation purposes. The LRP4 protein was expressed in CLL ( n = 66). Bioinformatic analysis scored LRP4 rs2306029 as a variant with possible deleterious and damaging variant of LRP4. LRP4 genotyping may help the recognition of patients with increased risk of RS at the time of CLL diagnosis. [ABSTRACT FROM AUTHOR]
- Published
- 2011
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23. Comparison of the in vitro effects of the anti-CD20 antibodies rituximab and GA101 on chronic lymphocytic leukaemia cells.
- Author
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Patz, Michaela, Isaeva, Polina, Forcob, Nche, Müller, Bianka, Frenzel, Lukas P., Wendtner, Clemens-Martin, Klein, Christian, Umana, Pablo, Hallek, Michael, and Krause, Günter
- Subjects
IMMUNOGLOBULINS ,MONOCLONAL antibodies ,RITUXIMAB ,LYMPHOCYTIC leukemia ,CELL death ,B cells ,PHYSIOLOGY ,LEUKEMIA treatment - Abstract
The effects of two CD20 antibodies, namely rituximab, the current standard for treatment of chronic lymphocytic leukaemia (CLL) in combination with chemotherapy, and GA101, a glyco-engineered type II antibody were compared on CLL cells ex vivo. Antibody-induced phosphatidylserine exposure was examined in isolated CLL cells. For a more comprehensive assessment of antibody-mediated cell killing including Fc-mediated mechanisms, B cell depletion from whole blood samples was monitored. Treatment with rituximab or GA101 reduced the average viability of isolated CLL cells by 6% or 11%, and the ratio of B to T cells in whole blood samples by 12% or 33%, respectively. Combination with GA101 enhanced the cytotoxicity of the chemotherapeutic agent chlorambucil on isolated CLL cells. CD20 surface expression on CLL cells correlated with GA101-induced B cell depletion, but not with direct cell death induction. Treatment of whole blood samples from CLL patients with a CpG-containing oligonucleotide increased CD20 expression on CLL cells and GA101-dependent B cell depletion. Despite the variable responses of individual CLL samples, the CLL cell depletion from whole blood by GA101 was consistently much stronger than by rituximab, which argues for clinical investigation of GA101 in CLL patients. [ABSTRACT FROM AUTHOR]
- Published
- 2011
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24. Silencing of ROR1 and FMOD with siRNA results in apoptosis of CLL cells A. Choudhury et al siRNA-Mediated Silencing of ROR1 and FMOD.
- Author
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Choudhury, Aniruddha, Derkow, Katja, Daneshmanesh, Amir Hossein, Mikaelsson, Eva, Kiaii, Shahryar, Kokhaei, Parviz, Österborg, Anders, and Mellstedt, Håkan
- Subjects
CHRONIC lymphocytic leukemia ,B cells ,MESSENGER RNA ,FIBROBLASTS ,CELL lines - Abstract
We have previously demonstrated that ROR1 and FMOD (fibromodulin) are two genes upregulated in chronic lymphocytic leukaemia (CLL) cells compared to normal blood B cells. In this study, siRNAs were used to specifically silence ROR1 and FMOD expression in CLL cells, healthy B cells and human fibroblast cell lines. siRNA treatment induced a specific reduction (75-95%) in FMOD and ROR1 mRNA. Western blot analysis with specific antibodies for FMOD and ROR1 demonstrated that the proteins were significantly downregulated 48 h after siRNA treatment. Silencing of FMOD and ROR1 resulted in statistically significant ( P ≤ 0·05-0·001) apoptosis of CLL cells but not of B cells from normal donors. Human fibroblast cell lines treated with FMOD and ROR1 siRNA did not undergo apoptosis. This is the first report demonstrating that ROR1 and FMOD may be involved in the survival of CLL cells. ROR1 in particular is further explored as potential target for therapy in CLL. [ABSTRACT FROM AUTHOR]
- Published
- 2010
- Full Text
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25. Patients with B cell chronic lymphocytic leukaemia have an expanded population of CD4+ perforin expressing T cells enriched for human cytomegalovirus specificity and an effector-memory phenotype.
- Author
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Walton, James A., Lydyard, Peter M., Nathwani, Amit, Emery, Vincent, Akbar, Arne, Glennie, Martin J., and Porakishvili, Nino
- Subjects
ANTINEOPLASTIC agents ,B cells ,LYMPHOCYTIC leukemia ,T cells ,CYTOMEGALOVIRUS diseases - Abstract
We have previously shown an expansion of cytotoxic antigen-experienced CD4
+ T cells (CTLs) that express perforin (PF) in the peripheral blood of patients with B cell chronic lymphocytic leukaemia (B-CLL). Increased frequencies of CD4+ CTLs have since been attributed to chronic viral infections, particularly, human cytomegalovirus (HCMV). The present study examined the involvement of CD4+ CTLs in responses to HCMV in B-CLL, and characterized their differentiation. We studied 36 HCMV seropositive (SP) and seronegative B-CLL patients and 20 healthy age-matched individuals. The HCMV reactivity of CD4+ PF+ and CD4+ PF− cells was determined by interferon-gamma expression, and expression of CD45RA and CCR7 was assessed by flow cytometry. Fluorescence in-situ hybridization was used to measure relative telomere lengths. CD4+ PF+ T cell expansion in B-CLL patients and controls was strongly associated with HCMV seropositivity. CD4+ PF+ compared to CD4+ PF− cells from SP B-CLL patients elicited major histocompatibility complex (MHC) class II-restricted responses to HCMV. CD4+ PF+ T cells from patients and controls were enriched with highly differentiated T-effector/memory (CCR7− ) and revertant (CCR7− CD45RA+ ) phenotype. CD4+ PF+ T cells from B-CLL patients had shorter telomeres than CD4+ PF− T cells, indicating an extensive replicative history. We conclude that persistent exposure to HCMV antigens in SP B-CLL patients leads to an expansion of the circulating MHC class II-restricted CD4+ PF+ T cell population with effector/memory phenotype. [ABSTRACT FROM AUTHOR]- Published
- 2010
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26. Solid organ transplant in individuals with monoclonal B-cell lymphocytosis and chronic lymphocytic leukaemia.
- Author
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Strati, Paolo, Gharaibeh, Kamel A., Leung, Nelson, Cosio, Ferdinando G., Call, Timothy G., and Shanafelt, Tait D.
- Subjects
CHRONIC lymphocytic leukemia ,B cells ,TRANSPLANTATION of organs, tissues, etc. ,IMMUNOGLOBULIN producing cells ,HEMODIALYSIS ,PATIENTS - Abstract
The article offers information on the transplant experience of monoclonal B-cell lymphocytosis and chronic lymphocytic leukaemia patients evaluated for solid organ transplant. Two patients experienced graft rejection and one of the two patients experienced graft failure and needed dialysis. The transplanted kidney was biopsied in this patient.
- Published
- 2016
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27. Impaired up-regulation of polo-like kinase 2 in B-cell chronic lymphocytic leukaemia lymphocytes resistant to fludarabine and 2-chlorodeoxyadenosine: a potential marker of defective damage response.
- Author
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de Viron, Emeline, Knoops, Laurent, Connerotte, Thierry, Smal, Caroline, Michaux, Lucienne, Saussoy, Pascale, Vannuffel, Pascal, Beert, Eline, Vekemans, Marie-Christiane, Hermans, Cédric, Bontemps, Françoise, and Van Den Neste, Eric
- Subjects
CHRONIC lymphocytic leukemia ,FLUDARABINE ,DNA damage ,B cells ,LYMPHOPROLIFERATIVE disorders - Abstract
The functional evaluation of ataxia telangiectasia mutated (ATM) and p53 was recently developed in B-cell chronic lymphocytic leukaemia (B-CLL), a disease in which the response to DNA damage is frequently altered. We identified a novel biomarker of chemosensitivity based on the induction of DNA damage by the purine nucleoside analogues (PNA) fludarabine and 2-chlorodeoxyadenosine (CdA). Using genome-wide expression profiling, it was observed that, in chemosensitive samples, PNA predominantly increased the expression of p53-dependent genes, among which PLK2 was the most highly activated at early time points. Conversely, in chemoresistant samples, p53-dependent and PLK2 responses were abolished. Using a quantitative real time polymerase chain reaction, we confirmed that PNA dose- and time-dependently increased PLK2 expression in chemosensitive but not chemoresistant B-CLL samples. Analysis of a larger cohort of B-CLL patients showed that cytotoxicity induced by PNA correlated well with PLK2 mRNA induction. Interestingly, we observed that failure to up-regulate PLK2 following PNA and chemoresistance were not strictly correlated with structural alterations in the TP53 gene. In conclusion, we propose that testing PLK2 activation after a 24-h incubation with PNA could be used to investigate the functional integrity of DNA damage-response pathways in B-CLL cells, and predict clinical sensitivity to these drugs. [ABSTRACT FROM AUTHOR]
- Published
- 2009
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28. Bi-directional activation between mesenchymal stem cells and CLL B-cells: implication for CLL disease progression.
- Author
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Ding, Wei, Nowakowski, Grzegorz S., Knox, Traci R., Boysen, Justin C., Maas, Mary L., Schwager, Susan M., Wu, Wenting, Wellik, Linda E., Dietz, Allan B., Ghosh, Asish K., Secreto, Charla R., Medina, Kay L., Shanafelt, Tait D., Zent, Clive S., Call, Timothy G., and Kay, Neil E.
- Subjects
LYMPHOCYTIC leukemia ,B cells ,APOPTOSIS ,PHOSPHORYLATION ,BONE marrow - Abstract
It was hypothesized that contact between chronic lymphocytic leukaemia (CLL) B-cells and marrow stromal cells impact both cell types. To test this hypothesis, we utilized a long-term primary culture system from bone biopsies that reliably generates a mesenchymal stem cell (MSC). Co-culture of MSC with CLL B-cells protected the latter from both spontaneous apoptosis and drug-induced apoptosis. The CD38 expression in previously CD38 positive CLL B-cells was up-regulated with MSC co-culture. Upregulation of CD71, CD25, CD69 and CD70 in CLL B-cells was found in the co-culture. CD71 upregulation was more significantly associated with high-risk CLL, implicating CD71 regulation in the microenvironment predicting disease progression. In MSC, rapid ERK and AKT phosphorylation (within 30 min) were detected when CLL B-cells and MSC were separated by transwell; indicating that activation of MSC was mediated by soluble factors. These findings support a bi-directional activation between bone marrow stromal cells and CLL B-cells. [ABSTRACT FROM AUTHOR]
- Published
- 2009
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- View/download PDF
29. Multiple isoforms of PAX5 are expressed in both lymphomas and normal B-cells.
- Author
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Arseneau, Jean-Ren, Laflamme, Mark, Lewis, Stephen M., Maïcas, Emmanuel, and Ouellette, Rodney J.
- Subjects
LYMPHOMAS ,B cells ,LYMPHOCYTES ,BIOMOLECULES ,LYMPHOCYTIC leukemia - Abstract
The transcription factor Pax5 plays a critical role in B cell development. It has been shown that alternative splicing of its gene ( PAX5) produces several distinct transcripts that modify the amino acid sequence of the putative Pax5 proteins. Subsequent studies have attempted to correlate the expression of PAX5 isoforms with certain B-cell lymphomas, the conclusions of which suggest that altered isoform expression is involved in lymphomagenesis. However, in the absence of definitive data for PAX5 isoform expression patterns in normal B cells it is difficult to confirm whether aberrant isoform expression can indeed be correlated with disease. Using a high-resolution method of analysis of reverse transcription polymerase chain reaction products, we sought to analyse the expression of the different PAX5 isoforms in normal B-cells as well as a number of B-cell lymphoma and chronic lymphocytic leukaemia cases. It was found that multiple PAX5 isoforms were expressed in both normal and malignant B cells. Immunodetection and polysomal RNA analyses also confirmed that the different PAX5 mRNAs were translated into their corresponding proteins. No consistent deregulation of PAX5 isoform expression was observed in B-cell lymphomas, but rather, complex isoform expression patterns were found in normal B cell as well as B-cell lymphoma and CLL cases. [ABSTRACT FROM AUTHOR]
- Published
- 2009
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- View/download PDF
30. Monoclonal B-cell lymphocytosis in first-degree relatives of patients with sporadic (non-familial) chronic lymphocytic leukaemia.
- Author
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Matos, Daniel M., Ismael, Sebastião J., Scrideli, Carlos A., de Oliveira, Fábio M., Rego, Eduardo M., and Falcão, Roberto P.
- Subjects
LYMPHOCYTIC leukemia ,LYMPHOPROLIFERATIVE disorders ,IN situ hybridization ,DNA polymerases ,LEUKEMIA - Abstract
Although biological similarities have been described among monoclonal B-cell lymphocytosis (MBL) and chronic lymphocytic leukaemia (CLL), the relationships between these two conditions are not fully understood, and new epidemiological studies in different populations and different countries continue to be reported. Here, we investigated 167 first-degree relatives from 42 families of patients with non-familial (sporadic) CLL, using four-colour flow cytometry. MBL was found in seven of 167 subjects (4·1%). Monoclonality was detected in all cases either by light-chain restriction or by polymerase chain reaction. Fluourescence in situ hybridization did not show any chromosomal abnormality. The prevalence of MBL according to age was 0 (0/54) in individuals aged less than 40 years, 2·5% (2/81) between 40 and 60 years, and 15·6% (5/32) in individuals over 60 years. The prevalence of MBL cases in individuals over 60 years was similar to that found in familial CLL relatives at the same age group. This suggests that in older first-degree relatives of patients with sporadic CLL, the risk of MBL detection is as high as in older first-degree relatives from CLL families, which could render these individuals belonging to ‘sporadic CLL families’ as susceptible as individuals from ‘familial CLL’ to the development of clinical CLL. [ABSTRACT FROM AUTHOR]
- Published
- 2009
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31. The prognosis of clinical monoclonal B cell lymphocytosis differs from prognosis of Rai 0 chronic lymphocytic leukaemia and is recapitulated by biological risk factors.
- Author
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Rossi, Davide, Sozzi, Elisa, Puma, Alessia, De Paoli, Lorenzo, Rasi, Silvia, Spina, Valeria, Gozzetti, Alessandro, Tassi, Maristella, Cencini, Emanuele, Raspadori, Donatella, Pinto, Valeria, Bertoni, Francesco, Gattei, Valter, Lauria, Francesco, Gaidano, Gianluca, and Forconi, Francesco
- Subjects
LYMPHOCYTIC leukemia ,B cells ,LYMPHOPROLIFERATIVE disorders ,CHRONIC lymphocytic leukemia ,GENOTYPE-environment interaction ,IN situ hybridization - Abstract
Monoclonal B-cell lymphocytosis (MBL) is an asymptomatic monoclonal expansion of <5·0 × 10
9 /l circulating CLL-phenotype B-cells. The relationship between MBL and Rai 0 CLL, as well as the impact of biological risk factors on MBL prognosis, are unknown. Out of 460 B-cell expansions with CLL-phenotype, 123 clinical MBL (cMBL) were compared to 154 Rai 0 CLL according to clinical and biological profile and outcome. cMBL had better humoral immune capacity and lower infection risk, lower prevalence of del11q22-q23/del17p13 and TP53 mutations, slower lymphocyte doubling time, and longer treatment-free survival. Also, cMBL diagnosis was a protective factor for treatment risk. Despite these favourable features, all cMBL were projected to progress, and lymphocytes <1·2 × 109 /l and >3·7 × 109 /l were the best thresholds predicting the lowest and highest risk of progression to CLL. Although IGHV status, CD38 and CD49d expression, and fluorescence in situ hybridization (FISH) karyotype individually predicted treatment-free survival, multivariate analysis identified the presence of +12 or del17p13 as the sole independent predictor of treatment requirement in cMBL (Hazard ratio: 5·39, 95% confidence interval 1·98–14·44, P = 0·001). Overall, these data showed that cMBL has a more favourable clinical course than Rai 0 CLL. Given that the biological profile can predict treatment requirement, stratification based on biological prognosticators may be helpful for cMBL management. [ABSTRACT FROM AUTHOR]- Published
- 2009
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- View/download PDF
32. The humanized CD40 antibody SGN-40 demonstrates pre-clinical activity that is enhanced by lenalidomide in chronic lymphocytic leukaemia.
- Author
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Lapalombella, Rosa, Gowda, Aruna, Joshi, Trupti, Mehter, Najma, Cheney, Carolyn, Lehman, Amy, Ching-Shih Chen, Johnson, Amy J., Caligiuri, Michael A., Tridandapani, Susheela, Muthusamy, Natarajan, and Byrd, John C.
- Subjects
IMMUNOGLOBULINS ,CHRONIC lymphocytic leukemia treatment ,CHRONIC leukemia ,DRUGS ,B cells ,MONOCLONAL antibodies ,LYMPHOMAS ,LEUKEMIA treatment - Abstract
Antibody-based therapies, such as rituximab and alemtuzumab, have contributed significantly to the treatment of Chronic Lymphocytic leukaemia (CLL). The CD40 antigen is expressed predominantly on B-cells and represents a potential target for immune-based therapies. SGN-40 is a humanized IgG1 monoclonal antibody currently in Phase I/II clinical trials for indolent lymphomas, diffuse large B cell lymphomas and Multiple Myeloma. Its biological effect on CLL cells has not been studied. The present study demonstrated that SGN-40 mediated modest apoptosis in a subset of patients with secondary cross-linking but did not mediate complement-dependent cytotoxicity. SGN-40 also mediated antibody-dependent cellular cytotoxicity (ADCC) predominantly through natural killer (NK) cells. Previous studies by our group and others have demonstrated that lenalidomide upregulates CD40 expression on primary B CLL cells and activates NK-cells. We therefore examined for the combinatorial effect of lenalidomide and SGN-40 and demonstrated that both enhanced direct apoptosis and ADCC against primary CLL B cells. These data together provide justification for clinical trials of SGN-40 and lenalidomide in combination for CLL therapy. [ABSTRACT FROM AUTHOR]
- Published
- 2009
- Full Text
- View/download PDF
33. Molecular and clinical features of chronic lymphocytic leukaemia with stereotyped B cell receptors: results from an Italian multicentre study.
- Author
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Bomben, Riccardo, Dal Bo, Michele, Capello, Daniela, Forconi, Francesco, Maffei, Rossana, Laurenti, Luca, Rossi, Davide, Del Principe, Maria Ilaria, Zucchetto, Antonella, Bertoni, Francesco, Rossi, Francesca Maria, Bulian, Pietro, Cattarossi, Ilaria, Ilariucci, Fiorella, Sozzi, Elisa, Spina, Valeria, Zucca, Emanuele, Degan, Massimo, Lauria, Francesco, and Del Poeta, Giovanni
- Subjects
CHRONIC lymphocytic leukemia ,B cells ,IMMUNOGLOBULINS ,MOLECULAR genetics ,CHRONIC diseases - Abstract
A fraction of chronic lymphocytic leukaemia (CLL) cases carry highly homologous B-cell receptors (BCR), i.e. characterized by non-random combinations of immunoglobulin heavy-chain variable ( IGHV) genes and heavy-chain complementarity determining region-3 (HCDR3), often associated with a restricted selection of IGVK/L light chains. Such ‘stereotyped’ BCR occur more frequently in CLL with unmutated (UM) than mutated (M) IGHV genes. We analysed 1426 IG rearrangements (from 1398 CLL cases) by a clustering driven by HCDR3 similarities. Molecular findings were correlated to time-to-treatment (TTT) and presence of known prognosticators. Sixty-nine clusters (319 IG-rearrangements, 22·4%) with stereotyped BCR were identified. Among 30 confirmed clusters (≥3 IG-rearrangements/cluster), we found 14 novel clusters, of which 11 had M IG rearrangements (M clusters) and predominantly (8/11) used IGHV3 subgroup genes. Recurrent cluster-biased amino acid changes were found throughout IGHV sequences of these ‘M clusters’. Regarding clinical outcome: (i) UM CLL from the IGHV1-2/1-3/1-18/1-46/7-4-1/IGKV1-39 cluster had poorer prognosis than UM/M cases, or UM cases using the same IGHV genes but not in clusters; (ii) M CLL from the IGHV3-21/IGLV3-21 cluster had TTT similar to UM CLL, and shorter than M CLL expressing IGHV3-21 but not in cluster. Altogether, our analysis identified additional molecular and clinical features for CLL expressing stereotyped BCR. [ABSTRACT FROM AUTHOR]
- Published
- 2009
- Full Text
- View/download PDF
34. Expression and function of toll like receptors in chronic lymphocytic leukaemia cells.
- Author
-
Muzio, Marta, Scielzo, Cristina, Bertilaccio, Maria T. S., Frenquelli, Michela, Ghia, Paolo, and Caligaris-Cappio, Federico
- Subjects
CHRONIC lymphocytic leukemia ,B cells ,CELL receptors ,IMMUNOCOMPETENT cells ,IMMUNE response ,CANCER cells ,APOPTOSIS - Abstract
Mature B-cells can recognize microbial antigens via B-cell-receptor (BCR) in a specific way and via Toll-like receptors (TLR) in a costimulatory manner. A wealth of information is gathering on the possible role of antigenic stimulation in the natural history of Chronic Lymphocytic Leukaemia (CLL). However little is known regarding the repertoire and function of TLR in CLL cells. The TLR family includes 10 different transmembrane proteins devoted to recognize specific pathogen-associated molecular patterns and to alarm immunocompetent cells to trigger an immune response. Here, we studied fresh leukaemic cells for the expression pattern of TLR1 to TLR10, NOD1, NOD2 and SIGIRR (also known as TIR8). CLL cells were found to express several pattern recognition receptors including TLR1, TLR2, TLR6, TLR10, NOD1 and NOD2. The specific TLR expressed by CLL cells were functional. Leukaemic cells, upon stimulation with TLR1/2/6 ligands, such as bacterial lipopeptides, activated the nuclear factor-κB signalling pathway, expressed CD86 and CD25 activation molecules, and were protected from spontaneous apoptosis. These findings further support the hypothesis that CLL cells resemble antigen-activated B-cells and suggest a potential role of TLR in modulating CLL cell response in the context of specific antigen recognition. [ABSTRACT FROM AUTHOR]
- Published
- 2009
- Full Text
- View/download PDF
35. Reduction of B cell turnover in chronic lymphocytic leukaemia.
- Author
-
Defoiche, Julien, Debacq, Christophe, Asquith, Becca, Zhang, Yan, Burny, Arsène, Bron, Dominique, Lagneaux, Laurence, Macallan, Derek, and Willems, Luc
- Subjects
B cells ,CHRONIC lymphocytic leukemia ,LYMPHOCYTES ,CELL proliferation ,DEUTERIUM - Abstract
Whether chronic lymphocytic leukaemia (CLL) is a latent or a proliferating disease has been intensively debated. Whilst the dogma that CLL results from accumulation of dormant lymphocytes is supported by the unresponsiveness of leukaemic cells to antigens and polyclonal activators, recent in vivo kinetic measurements indicate that B lymphocytes do divide at significant rates in CLL. However, an important and still unanswered question is whether CLL cells proliferate faster or slower compared with their normal counterparts. This report addressed directly this point and compared B-cell kinetics in CLL subjects and healthy controls, using a pulse-chase approach based on incorporation of deuterium from 6,6-
2 H2 -glucose into DNA. We confirmed that B cells proliferated at significant levels in CLL but found that the proliferation rates were reduced compared with healthy subjects (mean 0·47 vs. 1·31%/d respectively, P = 0·007), equivalent to an extended doubling time of circulating B cells (147 d vs. 53 d). In conclusion, CLL B cells proliferate at reduced levels compared with healthy controls. CLL is thus characterized by an aberrant B-cell kinetics with a decrease in cell turnover, an observation that may impact on elaboration of efficient therapeutic strategies. [ABSTRACT FROM AUTHOR]- Published
- 2008
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- View/download PDF
36. Biological and clinical risk factors of chronic lymphocytic leukaemia transformation to Richter syndrome.
- Author
-
Rossi, Davide, Cerri, Michaela, Capello, Daniela, Deambrogi, Clara, Rossi, Francesca Maria, Zucchetto, Antonella, De Paoli, Lorenzo, Cresta, Stefania, Rasi, Silvia, Spina, Valeria, Franceschetti, Silvia, Lunghi, Monia, Vendramin, Chiara, Bomben, Riccardo, Ramponi, Antonio, Monga, Guido, Conconi, Annarita, Magnani, Corrado, Gattei, Valter, and Gaidano, Gianluca
- Subjects
CHRONIC lymphocytic leukemia ,B cells ,LYMPHOMAS ,LYMPHOPROLIFERATIVE disorders ,REGRESSION analysis ,HOMOLOGY (Biology) - Abstract
Predictors of chronic lymphocytic leukaemia (CLL) transformation to Richter syndrome (RS) are not established and were investigated in 185 consecutive CLL cases. Actuarial incidence of RS ( n = 17; all diffuse large B-cell lymphomas) at 10 years was 16·2% (95% confidence interval: 8·0–24·4%). At CLL diagnosis, prognosticators of RS by univariate analysis were IGHV homology ≥98% ( P = 0·006), IGHV4-39 usage ( P < 0·001), del13q14 absence ( P = 0·004), expression of CD38 ( P < 0·001) and ZAP70 ( P = 0·004), size ( P < 0·001) and number ( P < 0·001) of lymph nodes, advanced Binet stage ( P = 0·002), and lactate dehydrogenase ( P < 0·001). Multivariate analysis, performed separately for biological and clinical variables, identified CD38 expression [Hazard ratio (HR) = 4·26; P = 0·018], IGHV4-39 usage (HR = 4·29; P = 0·018), and lymph node size ≥3 cm (HR = 9·07; P < 0·001) as independent RS prognosticators. A multivariate model simultaneously analysing biological and clinical variables identified lymph node size ≥3 cm (HR = 6·51; P = 0·001) and del13q14 absence (HR = 4·08; P = 0·031) as independent RS prognosticators. Risk factors of CLL transformation differed from risk factors of CLL progression. These results suggest that CD38 and del13q14 may identify biological subsets of CLL with different RS predisposition. Predominant nodal disease, CD38 expression, IGHV4-39 usage, and absence of del13q14 may help in predicting RS at CLL diagnosis. Close monitoring and a careful biopsy policy are needed in patients carrying transformation risk factors. [ABSTRACT FROM AUTHOR]
- Published
- 2008
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- View/download PDF
37. Chronic lymphocytic leukaemia: an overview of aetiology in light of recent developments in classification and pathogenesis.
- Author
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Linet, Martha S., Schubauer-Berigan, Mary K., Weisenburger, Dennis D., Richardson, David B., Landgren, Ola, Blair, Aaron, Silver, Sharon, Field, R. William, Caldwell, Glyn, Hatch, Maureen, and Dores, Graça M.
- Subjects
CHRONIC lymphocytic leukemia ,ETIOLOGY of diseases ,CARCINOGENESIS ,EPIDEMIOLOGY ,MONOCLONAL antibodies ,B cells ,CELL-mediated lympholysis ,IONIZING radiation - Abstract
This overview of the epidemiology of chronic lymphocytic leukaemia (CLL) summarizes the evolution of classification and coding systems and describes the intersection of pathogenesis and aetiology. The role of the putative precursor to CLL, monoclonal B-cell lymphocytosis (MBL), is considered, and ideas for future investigations of the MBL-CLL relationship are outlined. We discuss the epidemiology of CLL, focusing on descriptive patterns and methodological considerations. Postulated risk factors are reviewed including the role of ionizing and non-ionizing radiation, occupational and environmental chemical exposures, medical conditions and treatments, and lifestyle and genetic factors. We conclude by raising key questions that need to be addressed to advance our understanding of CLL aetiology. Recommendations for future epidemiological studies are given, including the standardization of reporting of CLL across cancer registries, the clarification of the natural history of MBL, and the circumvention of the methodological shortcomings of prior epidemiological investigations in relation to radiation, chemical exposures and infectious agents. [ABSTRACT FROM AUTHOR]
- Published
- 2007
- Full Text
- View/download PDF
38. Chronic lymphocytic leukaemia and small lymphocytic lymphoma: overview of the descriptive epidemiology.
- Author
-
Dores, Graça M., Anderson, William F., Curtis, Rochelle E., Landgren, Ola, Ostroumova, Evgenia, Bluhm, Elizabeth C., Rabkin, Charles S., Devesa, Susan S., and Linet, Martha S.
- Subjects
CHRONIC lymphocytic leukemia ,LYMPHOMAS ,EPIDEMIOLOGY ,B cells ,DISEASE incidence - Abstract
The 2001 World Health Organization classification scheme considers B-cell chronic lymphocytic leukaemia (CLL) and small lymphocytic lymphoma (SLL) in an aggregate category (CLL/SLL) because of shared clinicopathological features. We have estimated age-adjusted incidence rates (IRs) of CLL and SLL in the population-based Surveillance, Epidemiology and End Results Program in the United States to analyse patterns of CLL and SLL separately and jointly. Age-standardized to the 2000 US population, overall IRs were 3·83 per 100 000 person-years for CLL ( n = 15 676) and 1·31 for SLL ( n = 5382) during 1993–2004. Incidence of the combined entity, CLL/SLL, was 90% higher among males compared to females, and the male:female IR ratio was significantly higher for CLL (1·98) than for SLL (1·67). CLL/SLL IRs were 25% and 77% lower among Blacks and Asian/Pacific Islanders, respectively, compared to Whites. A significant reporting delay was evident for CLL but not for SLL, so that CLL/SLL temporal trends must be interpreted cautiously. CLL and SLL IRs increased exponentially with age among all gender/race groups, with CLL IRs increasing more steeply with advancing age than SLL. Avenues of future research include assessment of delayed- and under-reporting to cancer registries and exploration of race, gender, and age effects in epidemiological studies. [ABSTRACT FROM AUTHOR]
- Published
- 2007
- Full Text
- View/download PDF
39. B-cell repertoire and clonal analysis in unaffected first degree relatives in familial chronic lymphocytic leukaemia kindred.
- Author
-
Abbasi, Fatima, Longo, Nancy S., Lipsky, Peter E., Raveche, Elizabeth, Schleinitz, Therese A., Stetler-Stevenson, Maryalice, Caporaso, Neil, and Marti, Gerald
- Subjects
B cells ,FAMILIAL diseases ,CHRONIC lymphocytic leukemia ,MONOCLONAL antibodies ,CELL-mediated lympholysis ,FLOW cytometry ,POLYMERASE chain reaction ,IMMUNOGLOBULIN genes - Abstract
Monoclonal B cell lymphocytosis (MBL) was detected in four unaffected first-degree relatives (FDR) in a familial chronic lymphocytic leukaemia (CLL) kindred. The proband remains untreated and two male siblings have died. The four unaffected siblings have been followed for a five-year period. All four FDR developed a kappa
+ CD5+ MBL detected by flow cytometry. Poymerase chain reaction (PCR) for IGHV rearrangement showed evidence of oligoclonality in three of these individuals. Single cell PCR of flow cytometric sorted kappa+ cells combined with Ig kappa light chain gene sequencing revealed further evidence of monoclonality in two of these individuals. Three of these individuals all showed evidence of hyper-somatic mutations. The B-cell repertoire in unaffected FDR in familial CLL offers a new area to investigate the interface between the immune system and lymphoid neoplasm. [ABSTRACT FROM AUTHOR]- Published
- 2007
- Full Text
- View/download PDF
40. Bioethical considerations of monoclonal B-cell lymphocytosis: donor transfer after haematopoietic stem cell transplantation.
- Author
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Hardy, Nancy M., Grady, Christine, Pentz, Rebecca, Stetler-Stevenson, Maryalice, Raffeld, Mark, Fontaine, Laura S., Babb, Rebecca, Bishop, Michael R., Caporaso, Neil, and Marti, Gerald E.
- Subjects
BIOETHICS ,MONOCLONAL antibodies ,B cells ,CELL-mediated lympholysis ,HEMATOPOIETIC stem cell transplantation ,CHRONIC lymphocytic leukemia ,PHENOTYPES ,FLOW cytometry - Abstract
Monoclonal B-cell lymphocytosis (MBL) is a recently described laboratory finding in otherwise healthy individuals. In MBL, a light chain-restricted, clonal B-cell population, often with a chronic lymphocytic leukaemia (CLL) phenotype, is identified by flow cytometry. Although the prognostic significance remains unclear, there is an increased incidence in ageing populations and those with a family history of CLL. During the past decade of MBL study, three families have come to our attention in which prospective sibling haematopoietic stem cell donors were found to have an MBL. These families raise complex bioethical issues with regard to disclosure of research data, eligibility for clinical trials and potential donor transfer of MBL. These issues are explored in this report. Identification of MBL among prospective sibling transplant donors will become a common occurrence in transplant practice as transplantation is increasingly offered to older individuals and those with CLL. [ABSTRACT FROM AUTHOR]
- Published
- 2007
- Full Text
- View/download PDF
41. Monoclonal B-cell lymphocytosis in blood donors.
- Author
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Rachel, Jane M., Zucker, Marjorie L., Fox, Christopher M., Plapp, Fred V., Menitove, Jay E., Abbasi, Fatima, and Marti, Gerald E.
- Subjects
CELL-mediated lympholysis ,B cells ,BLOOD donors ,PHENOTYPES ,CHRONIC lymphocytic leukemia ,IMMUNOGLOBULINS ,BLOOD transfusion - Abstract
Monoclonal B-cell populations have been detected in the peripheral blood of apparently healthy individuals by flow cytometry. In 2005, the term monoclonal B-cell lymphocytosis (MBL) was proposed to describe these findings. MBL may be immunophenotypically similar to chronic lymphocytic leukaemia (CLL) and, like CLL, the prevalence is higher in males and older individuals. We studied the prevalence of MBL in blood donors from the Midwestern United States. Samples from 5141 donors were examined and seven (0·14%) were found to have immunophenotypic characteristics of MBL or CLL. Immunoglobulin heavy chain analysis yielded monoclonality or oligoclonality. Prior and subsequent to the study, an additional undetermined number of blood donors were screened and seven of these expressed immunophenotypic characteristics of MBL or CLL. We thus found a total of 14 healthy blood donors with monoclonal expansions of B-lymphocyte populations. Of these, 12 were presumptively classified as MBL and two as CLL. All but two of the donors were male; the mean age was 59 years. The clinical importance of these findings with regard to transfusion medicine has not been established. [ABSTRACT FROM AUTHOR]
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- 2007
- Full Text
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42. Rituximab and 17-allylamino-17-demethoxygeldanamycin induce synergistic apoptosis in B-cell chronic lymphocytic leukaemia.
- Author
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Johnson, Amy J., Wagner, Amy J., Cheney, Carolyn M., Smith, Lisa L., Lucas, David M., Guster, Sara K., Grever, Michael R., Lin, Thomas S., and Byrd, John C.
- Subjects
RITUXIMAB ,APOPTOSIS ,B cells ,CHRONIC lymphocytic leukemia ,DRUG resistance ,HEAT shock proteins ,MONOCLONAL antibodies ,PHARMACODYNAMICS - Abstract
Treatment options for chronic lymphocytic leukaemia (CLL) are limited and eventually fail because of the development of toxicities or drug resistance. Thus, identification of new therapeutic strategies and targets is a high priority. The semisynthetic geldanamycin derivative 17-allylamino-17-demethoxygeldanamycin (17-AAG) inhibits heat shock protein 90 (Hsp90) binding to client proteins, thereby leading to their degradation. We demonstrate that at biologically active and clinically attainable levels (1 μmol/l), 17-AAG treatment of CLL B cells in vitro causes modest apoptosis as well as decreased AKT protein levels. Given the potential activation of AKT following antibody therapy in CLL, we evaluated the combination of 17-AAG and rituximab. These agents produced synergistic cytotoxicity of CLL cells in vitro. However, rituximab-mediated antibody-dependent cellular cytotoxicity was modestly reduced with 17-AAG, and complement-dependent cytotoxicity was not altered. We conclude that the combination of Hsp90 inhibitors with therapeutic antibodies, such as rituximab may represent a novel strategy to enhance therapeutic response in CLL. Furthermore, our data indicates that AKT and Hsp70 protein levels are relevant pharmacodynamic endpoints to monitor the in vivo effect of 17-AAG therapy. [ABSTRACT FROM AUTHOR]
- Published
- 2007
- Full Text
- View/download PDF
43. The t(14;19)(q32;q13)-positive small B-cell leukaemia: a clinicopathologic and cytogenetic study of seven cases.
- Author
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Huh, Yang O., Abruzzo, Lynne V., Rassidakis, George Z., Parry-Jones, Nilima, Schlette, Ellen, Brito-Bapabulle, Vasantha, Matutes, Estella, Wotherspoon, Andrew, Keating, Michael J., Medeiros, L. Jeffrey, and Catovsky, Daniel
- Subjects
LEUKEMIA ,B cells ,CYTOGENETICS ,PATHOLOGY ,LYMPHOCYTES - Abstract
The t(14;19)(q32;q13), involving the BCL3 locus at chromosome 19q13 and the immunoglobulin heavy chain gene at 14q32, is a rare recurrent cytogenetic abnormality identified in B-cell neoplasms, most of which have been classified as chronic lymphocytic leukaemia (CLL) in the literature. We describe the clinicopathological, immunophenotypic and cytogenetic findings in seven patients with B-cell neoplasms associated with t(14;19)(q32;q13). There were five men and two women, with a median age of 48 years (range 33–68). All had absolute lymphocytosis, six had lymphadenopathy, and one had splenomegaly. Lymphocytes in blood and bone marrow aspirate smears were predominantly small and cytologically atypical. Flow cytometric immunophenotyping showed an atypical immunophenotype with low CLL scores. The growth pattern in bone marrow biopsy specimens was interstitial to diffuse; immunohistochemical stains were positive for bcl3 and negative for cyclin D1. Lymph node biopsy specimens of two patients revealed total architectural effacement by neoplasm with proliferation centres. In addition to t(14;19), cytogenetic studies demonstrated trisomy 12 in five patients. These results suggest that B-cell neoplasms with the t(14;19)(q32;q13) present frequently as leukaemia composed of small B-lymphocytes and share many features with CLL. However, these neoplasms also differ from CLL cytologically and in their immunophenotype. [ABSTRACT FROM AUTHOR]
- Published
- 2007
- Full Text
- View/download PDF
44. Heterogeneous intracellular expression of B-cell receptor components in B-cell chronic lymphocytic leukaemia (B-CLL) cells and effects of CD79b gene transfer on surface immunoglobulin levels in a B-CLL-derived cell line.
- Author
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Minuzzo, Sonia, Indraccolo, Stefano, Tosello, Valeria, Piovan, Erich, Cabrelle, Anna, Trentin, Livio, Semenzato, Giampietro, and Amadori, Alberto
- Subjects
CHRONIC lymphocytic leukemia ,CHRONIC diseases ,LYMPHOCYTIC leukemia ,B cells ,GENETIC transformation ,IMMUNOGLOBULINS - Abstract
B-cell chronic lymphocytic leukaemia (B-CLL) cells display low amounts of surface immunoglobulins (sIg). To investigate the mechanisms underlying this phenomenon, we performed a thorough study of surface and intracellular expression of the B-cell receptor (BCR) components in B-CLL cells using flow cytometry. There was an heterogeneous pattern of expression. Overall, 20 of 22 samples showed reduced sIgM levels, compared with normal B cells. Among them, three (15%) had very low to undetectable intracellular IgM levels and variable amounts of CD79a and CD79b; nine (45%) had low intracellular CD79b levels but appreciable levels of IgM and CD79a; and eight (40%) had relatively normal intracellular levels of all BCR components. To investigate whether surface BCR levels could be controlled by the rate of CD79b synthesis, adenoviral vectors encoding CD79b were generated and used for gene transfer experiments. Delivery of CD79b to non-B cells transfected with IgM and CD79a lead to high-level expression of a functional BCR. Moreover, CD79b gene transfer in a B cell line derived from a B-CLL patient and characterised by low intracellular levels of endogenous CD79b consistently increased sIgM levels. These findings indicate that the phenotype of B-CLL cells in a subset of patients may depend primarily on poor CD79b expression, and suggest that upregulation of CD79b expression may correct the phenotype of these cells. [ABSTRACT FROM AUTHOR]
- Published
- 2005
- Full Text
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45. Cytometry in monoclonal B-cell lymphocytosis and chronic lymphocytic leukaemia – The Hunting of the Snark?
- Author
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Shapiro, Howard M.
- Subjects
FLOW cytometry ,MONOCLONAL antibodies ,B cells ,CELL-mediated lympholysis ,CHRONIC lymphocytic leukemia ,BLOOD cells - Abstract
Cytometry has become important in the detection and determination of risk of monoclonal B-cell lymphocytosis; methodology has changed, and will continue to change, as cytometric technology changes. [ABSTRACT FROM AUTHOR]
- Published
- 2007
- Full Text
- View/download PDF
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