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Thomas P Loughran - One of the best experts on this subject based on the ideXlab platform.
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Never say die: survival signaling in Large Granular Lymphocyte leukemia.
Clinical lymphoma & myeloma, 2020Co-Authors: Mithun Vinod Shah, Ranran Zhang, Thomas P LoughranAbstract:Large Granular Lymphocyte (LGL) leukemia is a rare disorder of mature cytotoxic T or natural killer cells. Large Granular Lymphocyte leukemia is characterized by the accumulation of cytotoxic cells in blood and infiltration in the bone marrow, liver, and spleen. Herein, we review clinical features of LGL leukemia. We focus our discussion on known survival signals believed to play a role in the pathogenesis of LGL leukemia and their potential therapeutic implications.
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somatic stat3 mutations in felty syndrome an implication for a common pathogenesis with Large Granular Lymphocyte leukemia
Haematologica, 2017Co-Authors: Paula Savola, Thomas P Loughran, Oscar Bruck, Thomas Olson, Tiina Kelkka, M Kauppi, Panu E Kovanen, Soili Kytola, T Sokkaisler, M LeirisalorepoAbstract:Felty syndrome is a rare disease defined by neutropenia, splenomegaly, and rheumatoid arthritis. Sometimes the differential diagnosis between Felty syndrome and Large Granular Lymphocyte leukemia is problematic. Recently, somatic STAT3 and STAT5B mutations were discovered in 30-40% of patients with Large Granular Lymphocyte leukemia. We now aimed to study whether these mutations can also be detected in Felty syndrome, which would imply for a common pathogenic mechanism between these two disease entities. We collected samples and clinical information from 14 Felty syndrome patients who were monitored at the rheumatology outpatient clinic for Felty syndrome. Somatic STAT3 mutations were discovered in 43% (6/14) of Felty syndrome patients with deep amplicon sequencing targeting all STAT3 exons. Mutations were located in the SH2 domain of STAT3 which is a known mutational hotspot. No STAT5B mutations were found. In blood smears, overrepresentation of Large Granular Lymphocytes was observed, and in the majority of cases the CD8+ T-cell receptor repertoire was skewed when analyzed by flow cytometry. In bone marrow biopsies, an increased amount of phospho-STAT3 positive cells was discovered. Plasma cytokine profiling showed that 10 of the 92 assayed cytokines were elevated both in Felty syndrome and Large Granular Lymphocyte leukemia, and three of these cytokines were also increased in patients with uncomplicated rheumatoid arthritis. In conclusion, somatic STAT3 mutations and STAT3 activation are as frequent in Felty syndrome as in Large Granular Lymphocyte leukemia. Considering that the symptoms and treatment modalities are also similar, unified re-classification of these two syndromes is warranted.
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Pathogenesis of Autoimmune Diseases in Large Granular Lymphocyte Leukemia
Hematology, 2016Co-Authors: Thierry Lamy, Thomas P LoughranAbstract:Large Granular Lymphocyte (LGL) leukemia is often associated with autoimmune diseases. The clinical associations of autoimmune diseases occurring in LGL leukemia are reviewed. Current concepts regarding the pathogenesis of LGL leukemia are summarized. It is suggested that LGL leukemia can serve as a useful model of dysregulated apoptosis as an underlying mechanism for both malignancy and autoimmune disease.
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sphingosine kinase inhibitors decrease viability and induce cell death in natural killer Large Granular Lymphocyte leukemia
Cancer Biology & Therapy, 2015Co-Authors: Francis R Leblanc, Jeremy A Hengst, Valerie S Calvert, Emanuel F Petricoin, David J Feith, Thomas P LoughranAbstract:Sphingolipid metabolism has been identified as a potential therapeutic target in cancer. Sphingosine-1-phosphate (S1P) is a potent bioactive sphingolipid metabolite produced by sphingosine kinases-1 and −2 (SPHK1 and SPHK2). Elevated SPHK1 has been found in numerous cancer types and been shown to contribute to survival, chemotherapeutic resistance and malignancy. However, its role in Large Granular Natural Killer (NK) Large Granular Lymphocyte (LGL) leukemia has not been investigated. Here, we examine SPHK1 as a therapeutic target in LGL leukemia. We found that SPHK1 is overexpressed in peripheral blood mononuclear cells (PBMCs) from LGL leukemia patients which results in elevated S1P in the sera. The use of SPHK1 inhibitors, SKI-II or SKI-178, decreased leukemic NK cell viability and induced caspase-dependent apoptosis. SKI-II and SKI-178 restored the sphingolipid balance by increasing ceramide and decreasing S1P in leukemic NKL cells. SKI-II and SKI-178 also induced apoptosis in primary NK-LGLs from leu...
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the pathogenesis and treatment of Large Granular Lymphocyte leukemia
Blood Reviews, 2014Co-Authors: Steven N. Steinway, Francis R Leblanc, Thomas P LoughranAbstract:Abstract Large Granular Lymphocyte (LGL) leukemia is a spectrum of rare lymphoproliferative diseases of T Lymphocytes and natural killer cells. These diseases frequently present with splenomegaly, neutropenia, and autoimmune diseases like rheumatoid arthritis. LGL leukemia is more commonly of a chronic, indolent nature; however, rarely, they have an aggressive course. LGL leukemia is thought to arise from chronic antigen stimulation, which drives long-term cell survival through the activation of survival signaling pathways and suppression of pro-apoptotic signals. These include Jak-Stat, Mapk, Pi3k-Akt, sphingolipid, and IL-15/Pdgf signaling. Treatment traditionally includes immunosuppression with low dose methotrexate, cyclophosphamide, and other immunosuppressive agents; however, prospective and retrospective studies reveal very limited success. New studies surrounding Jak-Stat signaling suggest this may reveal new avenues for LGL leukemia therapeutics.
Jaroslaw P Maciejewski - One of the best experts on this subject based on the ideXlab platform.
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genomic landscape characterization of Large Granular Lymphocyte leukemia with a systems genetics approach
Leukemia, 2017Co-Authors: Alessandro Coppe, Emma I Andersson, Andrea Binatti, Vanessa Rebecca Gasparini, Stefania Bortoluzzi, Michael J Clemente, Marco Herling, Jaroslaw P MaciejewskiAbstract:Genomic landscape characterization of Large Granular Lymphocyte leukemia with a systems genetics approach
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deep sequencing of the t cell receptor repertoire in cd8 t Large Granular Lymphocyte leukemia identifies signature landscapes
Blood, 2013Co-Authors: Michael J Clemente, Marcin W Wlodarski, Bartlomiej P Przychodzen, Andres Jerez, Brittney Dienes, Manuel G Afable, Holleh D Husseinzadeh, Hanna Rajala, Satu Mustjoki, Jaroslaw P MaciejewskiAbstract:New massively parallel sequencing technology enables, through deep sequencing of rearranged T-cell receptor (TCR) Vβ complementarity-determining region 3 (CDR3) regions, a previously inaccessible level of TCR repertoire analysis. The CDR3 repertoire diversity reflects clonal composition, the potential antigenic recognition spectrum, and the quantity of available T-cell responses. In this context, T-Large Granular Lymphocyte (T-LGL) leukemia is a chronic clonal lymphoproliferation of cytotoxic T cells often associated with autoimmune diseases and various cytopenias. Using CD8+ T-LGL leukemia as a model disease, we set out to evaluate and compare the TCR deep-sequencing spectra of both patients and healthy controls to better understand how TCR deep sequencing could be used in the diagnosis and monitoring of not only T-LGL leukemia but also reactive processes such as autoimmune disease and infection. Our data demonstrate, with high resolution, significantly decreased diversity of the T-cell repertoire in CD8+ T-LGL leukemia and suggest that many T-LGL clonotypes may be private to the disease and may not be present in the general public, even at the basal level.
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mica polymorphism identified by whole genome array associated with nkg2d mediated cytotoxicity in t cell Large Granular Lymphocyte leukemia
Haematologica, 2010Co-Authors: Aaron D Viny, Michael J Clemente, Monika Jasek, M Askar, Hemant Ishwaran, Amy S Nowacki, Aiwen Zhang, Jaroslaw P MaciejewskiAbstract:Background Large Granular Lymphocyte leukemia is a semi-autonomous clonal proliferation of cytotoxic T cells accompanied by immune cytopenias and various autoimmune conditions. Due to the rarity of this disease and its association with autoimmune diseases, a theoretical germline or somatic mutation might have significant penetrance, thus enabling detection, even from samples of suboptimal size, through genome-wide association studies.Design and Methods To investigate a non-mendelian genetic predisposition to Large Granular Lymphocyte leukemia, we used a step-wise method for gene discovery. First, a modified ‘random forests’ technique was used for candidate gene identification: this was followed by traditional allele-specific polymerase chain reaction, sequencing modalities, and mechanistic assays.Results Our analysis found an association with MICA, a non-peptide-presenting, tightly regulated, stress-induced MHC-like molecule and cognate receptor for NKG2D, found abundantly on Large Granular Lymphocyte leukemia cells. Sequencing of germline DNA revealed a higher frequency of MICA*00801/A5.1 in patients with Large Granular Lymphocyte leukemia than in matched controls (64% versus 41%, P
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t nk Large Granular Lymphocyte leukemia and coexisting monoclonal b cell lymphocytosis like proliferations an unrecognized and frequent association
American Journal of Clinical Pathology, 2010Co-Authors: Matthew T Howard, Nelli Bejanyan, Jaroslaw P MaciejewskiAbstract:T-cell Large Granular Lymphocyte leukemia (T-LGLL) is a T-cell lymphoproliferative disorder that has recently been associated with B-cell dyscrasias on a spectrum ranging from dysgammaglobulinemia to lymphoma. To investigate the relationship between clonal B-cell and LGLL lymphoproliferations, we systematically studied Lymphocytes in 57 patients with T-LGLL or NK lymphocytosis using flow cytometric methods sensitive to low-level B-cell populations. We identified 16 patients (28%) with abnormal B-cell populations; 9 (16%) of the patients had no known history of a B-cell lymphoproliferative disorder. We characterized these abnormal B-cell populations as monoclonal B-cell lymphocytosis and report a high frequency of monoclonal B-cell lymphocytosis in T/NK LGLL. Our findings suggest that certain pathologic factors may operate in patients with T/NK LGLL to drive low-level clonal B-cell proliferations.
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diagnosis and therapy of neutropenia in Large Granular Lymphocyte leukemia
Current Opinion in Hematology, 2009Co-Authors: Sanjay R Mohan, Jaroslaw P MaciejewskiAbstract:Purpose of reviewT-cell Large Granular Lymphocyte leukemia is a chronic clonal lymphoproliferation of cytotoxic T cells often associated with immune-mediated cytopenias. The pathophysiology of cytopenias includes cytokine effects and direct antigen-specific cytotoxicity to hematopoietic precursors.
Y L Kwong - One of the best experts on this subject based on the ideXlab platform.
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indolent t cell Large Granular Lymphocyte leukaemia after haematopoietic sct a clinicopathologic and molecular analysis
Bone Marrow Transplantation, 2012Co-Authors: Harinder Gill, A H W Ip, Rock Y Y Leung, Jason C C So, Annie Pang, Anskar Y H Leung, Y L KwongAbstract:Indolent T-cell Large Granular Lymphocyte leukaemia after haematopoietic SCT: a clinicopathologic and molecular analysis
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Fludarabine, mitoxantrone and dexamethasone as first-line treatment for T-cell Large Granular Lymphocyte leukemia
Leukemia, 2007Co-Authors: J C W Chan, W Y Au, Annie Pang, Anskar Y H Leung, Y L KwongAbstract:Fludarabine, mitoxantrone and dexamethasone as first-line treatment for T-cell Large Granular Lymphocyte leukemia
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reversible paraneoplastic neuropathy associated with t cell Large Granular Lymphocyte leukemia
Neurology, 2004Co-Authors: W Y Au, S L Ho, S Y Leung, Y L KwongAbstract:T-cell Large Granular Lymphocyte (T-LGL) leukemia is a rare leukemia originating from CD3+, CD4−, and CD8+ T cells.1 It is an indolent disease often associated with autoimmune manifestations, including rheumatoid arthritis, neutropenia, and pure red cell aplasia (PRCA).2 Two unusual cases of T-LGL leukemia presented with prominent peripheral neuropathy, which improved significantly with successful leukemia treatment. Patient 1 was a 56-year-old man who sought treatment in 1996 for finger numbness, reduced dexterity, a severe glove and stocking sensory neuropathy extending to the elbow and knee, absent knee and ankle reflexes, but no motor weakness or ataxia. A blood count showed hemoglobin (Hb) 10.3 g/dL, white cell count (WCC) 3.5 × 109/L (60% of LGL), and platelet count (Plat) 210 × 109/L. The marrow was infiltrated by CD3+, CD4−, CD8+, and CD56− T cells with clonal T-cell receptor-γ (TCRγ) gene rearrangement, confirming the diagnosis of T-LGL leukemia. …
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association of pure red cell aplasia with t Large Granular Lymphocyte leukaemia
Journal of Clinical Pathology, 1998Co-Authors: Y L Kwong, Kin Fai Ellick WongAbstract:AIM: To define the relation between T Large Granular Lymphocyte (T-LGL) leukaemia and pure red cell aplasia in Chinese patients. METHODS: Patients with T-LGL leukaemia were identified from a consecutive series of Chinese patients with chronic lymphoproliferative disorders. The diagnosis of T-LGL leukaemia was based on typical morphological and immunophenotypical features, and confirmed by the detection of clonal T cell receptor gene rearrangement. The clinicopathological features, response to treatment, and long term follow up were also examined. RESULTS: Five patients were identified as having T-LGL leukaemia from a consecutive series of 33 Chinese patients with chronic lymphoproliferative disorders. The median follow up time was 45 months. An obvious lymphocytosis was present in only two cases, although an increase in Large Granular Lymphocytes in the peripheral blood was found in four. In one case, the LGL count was within the normal range. Epstein-Barr virus encoded early nuclear RNA was negative in all the cases. There was no evidence of rheumatoid arthritis, and none of the patients presented with recurrent infections. On follow up, pure red cell aplasia occurred at some stage of the disease in all the patients. This responded to treatment with cyclosporin A in two and with antithymocyte globulin in one. Two patients remained transfusion dependent. CONCLUSIONS: In contrast to Western patients, Chinese patients with T-LGL leukaemia do not appear to suffer from rheumatoid arthritis and recurrent infections, but pure red cell aplasia is a major cause of morbidity in this ethnic group.
Thierry Lamy - One of the best experts on this subject based on the ideXlab platform.
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Pathogenesis of Autoimmune Diseases in Large Granular Lymphocyte Leukemia
Hematology, 2016Co-Authors: Thierry Lamy, Thomas P LoughranAbstract:Large Granular Lymphocyte (LGL) leukemia is often associated with autoimmune diseases. The clinical associations of autoimmune diseases occurring in LGL leukemia are reviewed. Current concepts regarding the pathogenesis of LGL leukemia are summarized. It is suggested that LGL leukemia can serve as a useful model of dysregulated apoptosis as an underlying mechanism for both malignancy and autoimmune disease.
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hematopoietic stem cell transplantation for t cell Large Granular Lymphocyte leukemia a retrospective study of the european society for blood and marrow transplantation
Leukemia, 2016Co-Authors: Tony Marchand, Thierry Lamy, Herve Finel, W Arcese, Sylvain Choquet, J Finke, Anne Huynh, Giuseppe Irrera, Dimitrios Karakasis, J KonopackiAbstract:Hematopoietic stem cell transplantation for T-cell Large Granular Lymphocyte leukemia: a retrospective study of the European Society for Blood and Marrow Transplantation
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analysis of a french cohort of patients with Large Granular Lymphocyte leukemia a report on 229 cases
Haematologica, 2010Co-Authors: Benoit Bareau, Mohamed Hamidou, Jean Donadieu, Jeff Morcet, Oumedaly Reman, N Schleinitz, Olivier Tournilhac, Mikael Roussel, Thierry Fest, Thierry LamyAbstract:BACKGROUND: Large Granular Lymphocyte leukemia is a rare lymphoproliferative disorder associated with autoimmune diseases and impaired hematopoiesis. This study describes the clinical and biological characteristics of 229 patients with T-cell or NK-cell Large Granular Lymphocyte leukemia. DESIGN AND METHODS: The diagnosis was based on a Large Granular Lymphocyte expansion (> 0.5x10(9)/L) lasting more than 6 months. Monoclonal T-cell receptor gamma gene rearrangement was detected in all the cases of T-cell Large Granular Lymphocyte leukemia. Patients with chronic NK-cell lymphocytosis had an indolent disease, while those with multiorgan Large Granular Lymphocyte infiltration and an aggressive clinical disease were considered to have NK-cell Large Granular Lymphocyte leukemia. RESULTS: The diagnosis of T-cell Large Granular Lymphocyte leukemia was confirmed in 201 cases, chronic NK-cell lymphocytosis in 27 cases and NK-cell Large Granular Lymphocyte leukemia in one case. Associated autoimmune diseases or other neoplasms were present in 74 and 32 cases, respectively. One hundred patients (44%) required treatment, mainly for neutropenia-associated infections (n=45), symptomatic autoimmune diseases (n =24), transfusion-dependant anemia (n=18), and other causes (n=13). Patients were treated with steroids (n= 33), methotrexate (n=62), cytoxan (n=32), or cyclosporine (n=24) either as first-, second-, third- or fourth-line therapy. The overall response rate at 3 months and complete response rate for the various treatments were as follows: steroids (12% and 3%), methotrexate (55% and 21%), cytoxan (66% and 47%), cyclosporine (21% and 4%), respectively. Four out of 13 patients responded to splenectomy. Eleven out of 15 patients responded to cytoxan after methotrexate treatment had failed. The mean number of treatments was 3.4 (range, 1-7). There were 15 Large Granular Lymphocyte leukemia-related deaths. CONCLUSIONS: Patients with T-cell Large Granular Lymphocyte leukemia and chronic NK-cell lymphocytosis have similar clinical and biological features and responses to treatment. First-line therapy with cytoxan should be tested in a prospective trial.
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clinical features of Large Granular Lymphocyte leukemia
Seminars in Hematology, 2003Co-Authors: Thierry Lamy, Thomas P LoughranAbstract:Abstract The spectrum of Large Granular Lymphocyte (LGL) proliferations consists of four distinct entities: reactive/transient LGL expansion, chronic LGL lymphocytosis, classical indolent LGL leukemia, and aggressive LGL leukemia. LGL leukemias are classified as lymphoid malignancies. They are divided into CD3 + /T-cell LGL (85% of cases) and CD3 − /natural killer (NK) cell LGL leukemia (15% of cases). Recent progress in the comprehension of the leukemogenesis has shown a dysregulation of survival signals in leukemic cells. Identification of LGL expansion has been improved using T-cell receptor (TCR)β/γ polymerase chain reaction (PCR) analysis and a combination of Vβ and killer cell immunoglobulin-like receptor (KIR)-specific monoclonal antibodies. LGL leukemias are characterized by a clonal LGL infiltration of the bone marrow, spleen, and liver. Monoclonality is recognized by phenotypic, molecular, and karyotypic analysis. T-LGL leukemias affect the elderly and display a relatively indolent behavior. Approximately 60% to 70% of patients are symptomatic: recurrent infections secondary to chronic neutropenia, anemia, and autoimmune disease such as rheumatoid arthritis are the main clinical manifestations. Long-lasting remission can be obtained with low-dose methotrexate, cyclosporine A, or cyclophosphamide. Conversely, NK LGL leukemias behave aggressively, and most patients do not respond to chemotherapy.
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clinicopathological features of aggressive Large Granular Lymphocyte leukaemia resemble fas ligand transgenic mice
British Journal of Haematology, 2000Co-Authors: Thierry Lamy, Gianpietro Semenzato, Renato Zambello, Frank A Bauer, Yongxiang Li, Eric Pillemer, Homayoon Shahidi, Stephanie A Gregory, R Marcolongo, Thomas P LoughranAbstract:Fas ligand triggers cell death after interaction with its receptor Fas. Altered expression of Fas has been associated with lymphoproliferation and autoimmune disorders in both mice and man. Apoptosis of lung and liver tissue is seen in Fas ligand transgenic mice. It is not known whether constitutive expression of Fas ligand can cause a similar human disease. Four patients with aggressive Large Granular Lymphocyte (LGL) leukaemia involving lung and liver were studied. All four patients were severely ill with pulmonary involvement. Two patients presented with hypoxia and were oxygen dependent; the other two patients had severe pulmonary hypertension. Lung biopsies showed interstitial infiltration by leukaemic LGL. The infiltrating Lymphocytes expressed both Fas and Fas ligand, whereas normal pneumocytes expressed only Fas. Similar findings were observed in liver biopsies from these patients. Features mimicking the pathological changes of graft-versus-host disease were observed, including pneumocyte apoptosis. All four patients had high levels of circulating Fas ligand. Successful treatment with oral methotrexate or 2-chlorodeoxyadenosine was associated with disappearance or marked reduction of circulating Fas ligand. These results suggest that dysregulated expression of Fas ligand can lead to human disease with pathological features resembling graft-versus-host disease.
Ronald Paquette - One of the best experts on this subject based on the ideXlab platform.
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clonal drift demonstrates unexpected dynamics of the t cell repertoire in t Large Granular Lymphocyte leukemia
Blood, 2011Co-Authors: Michael J Clemente, Nelli Bejanyan, Marcin W Wlodarski, Aaron D Viny, Hideki Makishima, Isabell Bretschneider, Mohammad Shaik, Alan E Lichtin, Ronald PaquetteAbstract:T-cell Large Granular Lymphocyte leukemia (T-LGLL) is characterized by chronic lymphoproliferation of cytotoxic T Lymphocytes (CTLs) and is associated with lineage-restricted cytopenias. Introduction of T-cell receptor (TCR) variable β-chain (Vβ) monoclonal antibodies has facilitated identification and enumeration of clonal CTLs by flow cytometry. A highly skewed TCR Vβ repertoire identified by flow cytometry is strongly associated with monoclonal CDR3 regions by quantitative sequencing and positive TCRγ rearrangement assays. Therefore, Vβ expansions can serve as surrogate markers of CTL clonality to assess clonal kinetics in T-LGLL. We analyzed the TCR repertoire in 143 patients, 71 of which were available for serial measurements over 6 to 96 months. Although the majority (38/71, 54%) maintained a consistent monoclonal expansion, many (26/71, 37%) unexpectedly displayed a change in the dominant clone, whereby the original CTL clone contracted and another emerged as demonstrated by Vβ typing. Our results demonstrate that the T-cell repertoire is more dynamic in T-LGLL than recognized previously, illustrating the heterogeneity of disorders under this categorization.
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acquired amegakaryocytic thrombocytopenia and pure red cell aplasia associated with an occult Large Granular Lymphocyte leukemia
Leukemia Research, 2008Co-Authors: Thomas P Loughran, Jaroslaw P Maciejewski, Sebastian Sasu, Sophie X Song, P K Eplingburnette, Ronald PaquetteAbstract:Acquired amegakaryocytic thrombocytopenia and pure red cell aplasia rarely occur concurrently. We report a case in which these disorders were associated with an occult Large Granular Lymphocyte leukemia. The peripheral blood cytopenias improved after glucocorticoids and intravenous immunoglobulin were administered, and response was maintained with cyclosporine. Large Granular Lymphocyte leukemia should be suspected in the setting of unexplained bone marrow failure.
