scholarly journals Large granular lymphocytic leukemia: molecular pathogenesis, clinical manifestations, and treatment

Hematology ◽  
2012 ◽  
Vol 2012 (1) ◽  
pp. 652-659 ◽  
Author(s):  
Dan Zhang ◽  
Thomas P. Loughran
Keyword(s):  
Clinical Manifestations ◽  
Lymphocytic Leukemia ◽  
Therapeutic Options ◽  
Term Survival ◽  
Therapeutic Modalities ◽  
Activation Induced Cell Death ◽  
Chronic Antigenic Stimulation ◽  
Current State ◽  
Prospective Trials ◽  
Lgl Leukemia

Abstract Large granular lymphocyte (LGL) leukemia represents a spectrum of rare lymphoproliferative diseases defined by clonal amplification of either CD3+ cytotoxic T-lymphocytes or CD3− natural killer cells. This chapter focuses on the T-cell form of LGL leukemia. Clinical features include neutropenia, anemia, and rheumatoid arthritis. LGL leukemia is thought to arise from chronic antigenic stimulation, with the long-term survival of LGL being promoted by constitutive activation of multiple survival signaling pathways, such as the JAK/STAT3, sphingolipid, and Ras/MEK/ERK pathways. Therefore, these lead to global deregulation of apoptosis and resistance to normal pathways of activation-induced cell death. The majority of LGL leukemia patients eventually need treatment. Treatment of leukemic LGL is based on immunosuppressive therapy, primarily using low doses of methotrexate or cyclophosphamide. However, no standard therapy has been established because of the lack of large, prospective trials. In addition, because some patients are refractory to currently available treatments and none of these therapeutic modalities can cure LGL leukemia, new therapeutic options are needed. Understanding the current state of the pathogenesis of LGL leukemia may provide insights into novel therapeutic options.

scholarly journals How I treat LGL leukemia

Blood ◽  
2011 ◽  
Vol 117 (10) ◽  
pp. 2764-2774 ◽  
Author(s):  
Thierry Lamy ◽  
Thomas P. Loughran
Keyword(s):  
Treatment Options ◽  
Initial Therapy ◽  
Severe Neutropenia ◽  
Effector Memory ◽  
Therapeutic Modalities ◽  
Activation Induced Cell Death ◽  
Interleukin 15 ◽  
New Treatment ◽  
Patients Experience ◽  
Lgl Leukemia

AbstractLarge granular lymphocyte (LGL) leukemia is characterized by a clonal expansion of either CD3+ cytotoxic T or CD3− NK cells. Prominent clinical features of T-LGL leukemia include neutropenia, anemia and rheumatoid arthritis (RA). The terminal effector memory phenotype (CD3+/CD45RA+/CD62L−CD57+) of T-LGL suggests a pivotal chronic antigen-driven immune response. LGL survival is then promoted by platelet-derived growth factor and interleukin-15, resulting in global dysregulation of apoptosis and resistance to normal pathways of activation-induced cell death. These pathogenic features explain why treatment of T-LGL leukemia is based on immunosuppressive therapy. The majority of these patients eventually need treatment because of severe or symptomatic neutropenia, anemia, or RA. No standard therapy has been established because of the absence of large prospective trials. The authors use low-dose methotrexate initially for T-LGL leukemia patients with neutropenia and/or RA. We recommend either methotrexate or oral cyclophosphamide as initial therapy for anemia. If treatment is not successful, patients are switched to either the other agent or cyclosporine. The majority of patients experience an indolent clinical course. Deaths infrequently occur because of infections related to severe neutropenia. As there are no curative therapeutic modalities for T-LGL leukemia, new treatment options are needed.

scholarly journals Molecular profiling of LGL leukemia reveals role of sphingolipid signaling in survival of cytotoxic lymphocytes

Blood ◽  
2008 ◽  
Vol 112 (3) ◽  
pp. 770-781 ◽  
Author(s):  
Mithun Vinod Shah ◽  
Ranran Zhang ◽  
Rosalyn Irby ◽  
Ravi Kothapalli ◽  
Xin Liu ◽  
...  
Keyword(s):  
Mononuclear Cells ◽  
Gene Expression Signature ◽  
Effector Memory ◽  
Cytotoxic Lymphocytes ◽  
Peripheral Blood Mononuclear ◽  
Term Survival ◽  
Memory Cytotoxic T Lymphocytes ◽  
Induced Apoptosis ◽  
Lgl Leukemia

Abstract T-cell large granular lymphocyte (LGL) leukemia is characterized by clonal expansion of CD3+CD8+ cells. Leukemic LGLs correspond to terminally differentiated effector-memory cytotoxic T lymphocytes (CTLs) that escape Fas-mediated activation-induced cell death (AICD) in vivo. The gene expression signature of peripheral blood mononuclear cells from 30 LGL leukemia patients showed profound dysregulation of expression of apoptotic genes and suggested uncoupling of activation and apoptotic pathways as a mechanism for failure of AICD in leukemic LGLs. Pathway-based microarray analysis indicated that balance of proapoptotic and antiapoptotic sphingolipid-mediated signaling was deregulated in leukemic LGLs. We further investigated sphingolipid pathways and found that acid ceramidase was constitutively overexpressed in leukemic LGLs and that its inhibition induced apoptosis of leukemic LGLs. We also showed that S1P5 is the predominant S1P receptor in leukemic LGLs, whereas S1P1 is down-regulated. FTY720, a functional antagonist of S1P-mediated signaling, induced apoptosis in leukemic LGLs and also sensitized leukemic LGLs to Fas-mediated death. Collectively, these results show a role for sphingolipid-mediated signaling as a mechanism for long-term survival of CTLs. Therapeutic targeting of this pathway, such as use of FTY720, may have efficacy in LGL leukemia.

scholarly journals Clinical improvement by farnesyltransferase inhibition in NK large granular lymphocyte leukemia associated with imbalanced NK receptor signaling

Blood ◽  
2008 ◽  
Vol 112 (12) ◽  
pp. 4694-4698 ◽  
Author(s):  
P. K. Epling-Burnette ◽  
Lubomir Sokol ◽  
Xianhong Chen ◽  
Fanqi Bai ◽  
Junmin Zhou ◽  
...  
Keyword(s):  
Pulmonary Artery ◽  
Clinical Manifestations ◽  
Erythroid Differentiation ◽  
Pulmonary Artery Hypertension ◽  
Large Granular Lymphocyte ◽  
Receptor Signaling ◽  
Pulmonary Endothelial Cells ◽  
First Case ◽  
Nk Receptor ◽  
Lgl Leukemia

Abstract Large granular lymphocyte (LGL) leukemia is commonly associated with poor hematopoiesis. The first case of pulmonary artery hypertension (PAH) was observed in a 57-year-old woman with natural killer (NK)–LGL leukemia and transfusion-dependent anemia. Using a genetic approach, we demonstrated that killing of pulmonary endothelial cells by patient NK cells was mediated by dysregulated balance in activating and inhibitory NK-receptor signaling. Elevated pulmonary artery pressure and erythroid differentiation improved after disrupting the NK-receptor signaling pathway with 4 courses of a farnesyltransferase inhibitor, tipifarnib. Coincidental association between PAH and LGL leukemia suggest a causal relationship between the expanded lymphocyte population and these clinical manifestations. This trial is registered at www.ClinicalTrials.gov as NCI 6823.

Foot tendinopathies in rheumatic diseases: etiopathogenesis, clinical manifestations and therapeutic options

2012 ◽  
Vol 32 (5) ◽  
pp. 547-555 ◽  
Author(s):  
A. Frizziero ◽  
V. Bonsangue ◽  
M. Trevisan ◽  
P. R. J. Ames ◽  
S. Masiero
Keyword(s):  
Rheumatic Diseases ◽  
Clinical Manifestations ◽  
Therapeutic Options

scholarly journals Clinical manifestations in two patients with pyruvate dehydrogenase deficiency and long-term survival

2017 ◽  
Vol 4 (1) ◽  
Author(s):  
Takanobu Yoshida ◽  
Jun Kido ◽  
Hiroshi Mitsubuchi ◽  
Shirou Matsumoto ◽  
Fumio Endo ◽  
...  
Keyword(s):  
Pyruvate Dehydrogenase ◽  
Dehydrogenase Deficiency ◽  
Clinical Manifestations ◽  
Pyruvate Dehydrogenase Deficiency ◽  
Term Survival ◽  
Long Term Survival

scholarly journals Working with guilt and shame

2012 ◽  
Vol 18 (2) ◽  
pp. 137-143 ◽  
Author(s):  
Andrew Clark
Keyword(s):  
Clinical Manifestations ◽  
Mental Healthcare ◽  
Therapeutic Options ◽  
Psychological Therapies ◽  
Psychological Experiences

SummaryThis article describes the psychological experiences of guilt and shame. Although these affects have an important role in holding our communities together, they can also become extremely distressing and debilitating for individuals. As such, they are transdiagnostic problems which are frequently encountered in mental healthcare. The origin of these affects is considered from religious, cultural and psychological perspectives. The article then explores the clinical manifestations of guilt and shame. Finally, consideration is given to therapeutic options, including general approaches as well as specific psychological therapies.

scholarly journals No improvement in long-term survival over time for chronic lymphocytic leukemia patients in stereotyped subsets #1 and #2 treated with chemo(immuno)therapy

Haematologica ◽  
2017 ◽  
Vol 103 (4) ◽  
pp. e158-e161 ◽  
Author(s):  
Panagiotis Baliakas ◽  
Mattias Mattsson ◽  
Anastasia Hadzidimitriou ◽  
Eva Minga ◽  
Andreas Agathangelidis ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Lymphocytic Leukemia ◽  
Term Survival ◽  
Long Term Survival ◽  
Over Time

scholarly journals Expression of the apoptosis-releated genes in patients with newly diagnosed chronic lymphocytic leukemia in clinical data context

2018 ◽  
Vol 17 (2) ◽  
pp. 41-46 ◽  
Author(s):  
S. G. Zakharov ◽  
A. K. Golenkov ◽  
A. V. Misyurin ◽  
E. V. Kataeva ◽  
A. A. Rudakova ◽  
...  
Keyword(s):  
Gene Expression ◽  
Clinical Manifestations ◽  
Multivariate Regression Analysis ◽  
Lymphocytic Leukemia ◽  
Newly Diagnosed ◽  
Expression Of Genes ◽  
Gene Level ◽  
Genes Encoding ◽  
Group Ii ◽  
High Level

Introduction.The given data of fundamental studies of apoptosis processes in B-cell lymphocytic leukemia (B-CLL) testifies about the complexity and variety of mechanisms affecting the kinetics of normal cells and tumor lymphocytes in this disease. It is important to study the severity of clinical manifestations of the disease depending on the expression of the genes that modulate apoptosis.The purposeof the study is to compare the activity of genes encoding apoptosis modulators, the cell cycle and cancer-testicular PRAME protein with clinical manifestations of the disease in primary patients with B-CLL.Materials and methods.The level of expression of the proapoptotic genes FAS, TRAIL, TNFR2, DR4/5 and DR3, as well as the HSP27, XIAP genes, blocking apoptosis was determined in 23 patients with newly diagnosed chronic B-CLL. In addition, expression of genes TP53 and P21 and cancer-testis gene PRAME are tested.Results.According to the multivariate regression analysis, the FAS gene expression in the onset of the disease had the greatest impact on the clinical characteristics of the disease. In this connection, the patients were divided into groups with normal (group) and low gene level (group II). A low level of FAS expression (Me 387 %) was associated with stage II disease (p = 0.03), a large number of lympho cytes (p = 0.001), fewer erythrocytes (p = 0.08), and a lower level of TNFR2 gene expression (p = 0.08), high level of expression of XIAP, HSP27, P21. Overall, the anti-apoptotic potential in Group II patients was higher, which was accompanied by more pronounced clinical manifestations of the disease.Conclusions.The increased anti-apoptotic potential of tumor lymphocytes in newly diagnosed B-CLL is accompanied by a larger tumor mass and greater clinical and hematological manifestation of the disease.

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