scholarly journals STAT3 and STAT5B Mutations in T/NK-Cell Chronic Lymphoproliferative Disorders of Large Granular Lymphocytes (LGL): Association with Disease Features

Cancers ◽  
2020 ◽  
Vol 12 (12) ◽  
pp. 3508
Author(s):  
Noemí Muñoz-García ◽  
María Jara-Acevedo ◽  
Carolina Caldas ◽  
Paloma Bárcena ◽  
Antonio López ◽  
...  
Keyword(s):  
Nk Cell ◽  
Lymphoproliferative Disorders ◽  
Lymphocytic Leukemia ◽  
Severe Neutropenia ◽  
Large Granular Lymphocytes ◽  
Healthy Donors ◽  
High Prevalence ◽  
Stat3 Mutations ◽  
Granular Lymphocytes ◽  
Normal Leukocyte

STAT3 and STAT5B (STAT3/STAT5B) mutations are the most common mutations in T-cell large granular lymphocytic leukemia (T-LGLL) and chronic lymphoproliferative disorders of NK cells (CLPD-NK), but their clinical impact remains unknown. We investigated the frequency and type of STAT3/STAT5B mutations in FACS-sorted populations of expanded T/NK-LGL from 100 (82 clonal; 6 oligoclonal; 12 polyclonal) patients, and its relationship with disease features. Seventeen non-LGL T-CLPD patients and 628 age-matched healthy donors were analyzed as controls. STAT3 (n = 30) and STAT5B (n = 1) mutations were detected in 28/82 clonal T/NK-LGLL patients (34%), while absent (0/18, 0%) among oligoclonal/polyclonal LGL-lymphocytosis. Mutations were found across all diagnostic subgroups: TCD8+-LGLL, 36%; CLPD-NK, 38%; TCD4+-LGLL, 7%; Tαβ+DP-LGLL, 100%; Tαβ+DN-LGLL, 50%; Tγδ+-LGLL, 44%. STAT3-mutated T-LGLL/CLPD-NK showed overall reduced (p < 0.05) blood counts of most normal leukocyte subsets, with a higher rate (vs. nonmutated LGLL) of neutropenia (p = 0.04), severe neutropenia (p = 0.02), and cases requiring treatment (p = 0.0001), together with a shorter time-to-therapy (p = 0.0001), particularly in non-Y640F STAT3-mutated patients. These findings confirm and extend on previous observations about the high prevalence of STAT3 mutations across different subtypes of LGLL, and its association with a more marked decrease of all major blood-cell subsets and a shortened time-to-therapy.

Decreased expression of bcl-2 (p26) in CD8(+) lymphocytes of patients with T-cell lymphoproliferative disorders of large granular lymphocytes

1997 ◽  
Vol 15 (2) ◽  
pp. 81-91 ◽  
Author(s):  
Margarida Lima ◽  
Maria Dos Anjos Teixeira ◽  
Ana Helena Ribeiro Dos Santos ◽  
Maria Luís Queirós ◽  
Benvindo Justiça
Keyword(s):  
T Cell ◽  
Lymphoproliferative Disorders ◽  
Large Granular Lymphocytes ◽  
Granular Lymphocytes

scholarly journals Expression of a NK cell-restricted epitope on decidual large granular lymphocytes

1996 ◽  
Vol 8 (10) ◽  
pp. 1637-1642 ◽  
Author(s):  
Sabine Calatayud ◽  
Eric Vivier ◽  
Janine Bernaud ◽  
Yves Mérieux ◽  
Dominique Rigal
Keyword(s):  
Nk Cell ◽  
Large Granular Lymphocytes ◽  
Granular Lymphocytes ◽  
Restricted Epitope

scholarly journals Lysis of lymphoma cells by autologous and allogeneic natural killer cells

Blood ◽  
1985 ◽  
Vol 65 (3) ◽  
pp. 638-643
Author(s):  
K Oshimi ◽  
Y Oshimi ◽  
O Yamada ◽  
H Mizoguchi
Keyword(s):  
Nk Cells ◽  
Natural Killer ◽  
Culture Medium ◽  
Large Granular Lymphocytes ◽  
Antibody Treatment ◽  
Lymphoma Cells ◽  
Effector Cells ◽  
Healthy Donors ◽  
Cytotoxic Effector ◽  
Granular Lymphocytes

Studies were undertaken to determine whether natural killer (NK) cells would lyse autologous and allogeneic lymphoma cells. When large granular lymphocytes, which are known to mediate NK activity, were enriched from peripheral blood and used as effector cells, they lysed autologous lymphoma cells of all of eight patients tested, and those of healthy donors lysed lymphoma cells of all of ten patients tested. The addition of interferon to the culture medium enhanced their cytotoxicity in three of the eight patients in the autologous effector- tumor system and in four of the ten patients in the above allogeneic system. On the basis of the unlabeled target competition test and the decrease in cytotoxicity with anti-NK antibody treatment, NK cells appeared to be the main cytotoxic effector cells for autologous and allogeneic lymphoma cells.

4-1BB Ligand Mediates a “Vicious Cycle” of Immune Evasion Upon Reciprocal Interaction of Chronic Lymphocytic Leukemia and NK Cells

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2416-2416
Author(s):  
Corina Buechele ◽  
Tina Baessler ◽  
Benjamin J Schmiedel ◽  
Lothar Kanz ◽  
Helmut R. Salih
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Nk Cells ◽  
Immune Evasion ◽  
Nk Cell ◽  
Lymphocytic Leukemia ◽  
Antibody Treatment ◽  
Cell Reactivity ◽  
Allogenic Stem Cell Transplantation ◽  
Immunoregulatory Cytokines ◽  
Healthy Donors

Abstract Abstract 2416 NK cells play an important role in tumor immunosurveillance. Their reactivity is governed by various immunoregulatory molecules, which influence both direct anti-tumor immunity and NK responses induced by therapeutic antibodies like Rituximab. Various members of the TNF/TNFR family modulate differentiation, proliferation, activation, and death of both tumor and immune effector cells including NK cells. Recently we reported that the TNFR family member 4-1BB/CD137 is expressed on human NK cells following activation. In contrast to the stimulatory role of its murine counterpart, we found that human 4-1BB impairs NK anti-tumor reactivity upon interaction with its ligand 4-1BBL expressed on blasts of a substantial proportion of acute myeloid leukemia patients (Blood 115: 3058-69; 2010). In addition, we found that expression of 4-1BBL is general feature of leukemic cells of chronic lymphocytic leukemia (CLL) patients causing impaired direct and Rituximab-induced NK cell reactivity (Blood 114: 279; 2009). Here we report that reverse signaling via 4-1BBL into CLL cells following interaction with 4-1BB, which is absent on NK cells of healthy donors, but expressed at substantial levels on NK cells of CLL patients, induced pronounced production of immunoregulatory cytokines like TNF, IL-6 and IL-8 by the CLL cells. Moreover, we found that sera of CLL patients contained elevated levels of these immunoregulatory cytokines as compared to healthy controls. When PBMC of healthy donors were exposed to supernatants of in vitro cultured CLL cells or sera from CLL patients, this resulted in pronounced 4-1BB expression on the NK cells. This effect could be prevented by addition of the TNF blocker Infliximab to patient sera. The 4-1BB expression induced by CLL sera resulted in impaired NK reactivity specifically against 4-1BBL-expressing targets as revealed by functional analyses with 4-1BBL transfectants and the respective mock-controls. Moreover, the induced 4-1BB expression also impaired NK cell reactivity against primary CLL cells constitutively expressing 4-1BBL, thus closing a cycle of immune evasion. Taken together, our data demonstrate that 4-1BBL enables CLL cells to evade NK anti-tumor reactivity, and disruption of the “vicious 4-1BB-4-1BBL cycle” in CLL - NK interaction e.g. by TNF- or 4-1BB-blockade may serve well to enhance NK reactivity in therapeutic strategies like antibody treatment or allogenic stem cell transplantation in CLL, which rely on sufficient NK cell function. Disclosures: No relevant conflicts of interest to declare.

Large Granular Lymphocyte Leukemia: Case Report of Chronic Neutropenia and Rheumatoid Arthritis-like Symptoms in a Child

2001 ◽  
Vol 4 (1) ◽  
pp. 94-99 ◽  
Author(s):  
Carol A. Blanchong ◽  
Randal Olshefski ◽  
Samir Kahwash
Keyword(s):  
Rheumatoid Arthritis ◽  
T Cell ◽  
Receptor Gene ◽  
Lymphoproliferative Disorders ◽  
Large Granular Lymphocyte ◽  
Large Granular Lymphocytes ◽  
Large Granular Lymphocyte Leukemia ◽  
Granular Lymphocytes ◽  
Chronic Neutropenia ◽  
Lgl Leukemia

Lymphoproliferative disorders of large granular lymphocytes (LGL) are heterogeneous, with a clinical/pathologic spectrum ranging from a benign polyclonal expansion to an aggressive clonal disease. Often these lymphoproliferative disorders are associated with autoimmune disease. The clonal form of the disorder, LGL leukemia, typically occurs in older adults with a median age of 55 years at diagnosis. Pediatric cases are referred to in review articles; however, no detailed reports of T-cell LGL leukemia in children exist. This report illustrates a case of a child who presented initially at age 2 and 1/2 years with psoriasis, juvenile rheumatoid arthritis-like symptoms, and neutropenia. Bone marrow examinations obtained throughout his course have demonstrated progressive hypercellularity with increased reticulin fibers and replacement of the normal marrow elements by lymphocytes, which were later identified as large granular lymphocytes. Further testing with immunophenotyping by flow cytometry and T-cell receptor gene rearrangement studies revealed a monoclonal proliferation of large granular lymphocytes and confirmed a diagnosis of LGL leukemia. Although rare, large granular lymphocyte leukemia should be included in the differential diagnosis of chronic neutropenia in children.

scholarly journals Ultrastructural and biochemical characterization of glycosaminoglycans in HNK-1-positive large granular lymphocytes

Blood ◽  
1985 ◽  
Vol 66 (1) ◽  
pp. 20-25 ◽  
Author(s):  
RT Parmley ◽  
F Rahemtulla ◽  
MD Cooper ◽  
L Roden
Keyword(s):  
Nk Cells ◽  
Nitrous Acid ◽  
Mononuclear Cells ◽  
Biochemical Characterization ◽  
Dermatan Sulfate ◽  
Nk Cell ◽  
Large Granular Lymphocytes ◽  
Specific Staining ◽  
Intense Staining ◽  
Granular Lymphocytes

Abstract Natural killer (NK) cells are large granular lymphocytes (LGLs) that contain distinct lysosomal granules. The present study was undertaken to determine if these lysosomes contain glycosaminoglycans (GAGs) similar to those previously described in myeloid cells. Mononuclear cells from human blood were stained with HNK-1 fluoresceinated monoclonal antibody, and the NK cell population reactive with this antibody were isolated with a fluorescence-activated cell sorter (FACS). Specific staining of sulfated macromolecules with the cationic reagent, high iron diamine, was observed in the lysosomal granules of 90% of the HNK-1 positive cells. Staining in the same location was also observed in the unsorted LGLs, presumed to be NK cells, and intense staining of the cell surface was also a prominent feature of these cells. Surface staining was not evident in the majority of the FACS- separated NK cells. Digestion with chondroitinase ABC or treatment with nitrous acid reduced the staining in both locations; after sequential treatment with both chondroitinase and nitrous acid, little or no staining was seen. The presence of chondroitin sulfate (and/or dermatan sulfate) and heparan sulfate was also shown by the finding that incubation of the isolated NK cells with 35S-sulfate yielded cell- associated radiolabeled macromolecules with the characteristics of these two groups of GAGs. Of the labeled GAG pool, 60% was degraded by chondroitinase and 40% was susceptible to nitrous acid treatment. LGLs of a patient with Chediak-Higashi syndrome was also stained, and intracellular sulfate staining was clearly localized to the enlarged granules, supporting the conclusion that the lysosomes are the major site of intracellular accumulation of GAGs in normal NK cells.

scholarly journals Accumulation of natural killer and cytotoxic T large granular lymphocytes in the liver during virus infection.

1986 ◽  
Vol 164 (5) ◽  
pp. 1667-1681 ◽  
Author(s):  
K W McIntyre ◽  
R M Welsh
Keyword(s):  
Natural Killer ◽  
Nk Cell ◽  
Hepatitis Virus ◽  
Murine Cytomegalovirus ◽  
Large Granular Lymphocytes ◽  
Cell Surface Antigens ◽  
Interferon Inducer ◽  
Fourfold Increase ◽  
Granular Lymphocytes ◽  
Ctl Activity

The immunologic mechanisms involved in virus-induced hepatitis were examined by measuring the cytotoxic capabilities and the morphologic and antigenic phenotypes of leukocytes isolated from livers of virus-infected mice. Large granular lymphocytes (LGL) of both natural killer (NK) cell and cytotoxic T lymphocyte (CTL) phenotypes were found to accumulate in livers of mice infected with either the nonhepatotropic Armstrong strain of lymphocytic choriomeningitis virus (LCMV-ARM) or the hepatotropic WE strain (LCMV-WE). Between days 1 and 5 postinfection (p.i.), both viruses induced a three- to fourfold increase in NK cell lytic activity in the livers of C3H/St mice and a three- to fourfold increase in the number of LGL in the organ. These LGL were characterized as NK cells on the basis of cell surface antigens, kinetics of appearance, target cell range, and morphology. By day 7 p.i., virus-specific, H-2-restricted, Thy-1+, Lyt-2+, CTL activity was present in the liver, and its appearance correlated with a second wave of LGL accumulation. CTL activity, total leukocyte number, and CTL/LGL number were at least fivefold higher in the livers of mice infected with LCMV-WE than with LCMV-ARM. The dramatic LCMV-WE-induced day 7 increases in total leukocytes and LGL were absent in athymic nude (nu/nu) mice, suggesting that the increases were T cell-dependent. LCMV-ARM infection of C57BL/6 mice induced significant spleen CTL activity but little liver CTL activity, whereas LCMV-WE infection resulted in significant liver CTL activity but minimal spleen CTL activity. Mice infected with the cytopathic hepatotropic viruses, mouse hepatitis virus (MHV) and murine cytomegalovirus (MCMV), experienced much greater increases in liver NK/LGL by day 3 p.i. than did mice infected with LCMV or injected with the interferon-inducer poly(I-C). MHV-infected mice homozygous for the beige (bg/bg) mutation also exhibited significant increases in liver NK/LGL cell number and activity, although the activity was less than heterozygote controls, and the morphology of the LGL granules was aberrant. These data show that the LGL accumulate in virus-infected organs, in this case, the liver. An early NK/LGL influx is most pronounced during infection with cytopathic hepatotropic viruses. This initial influx of NK/LGL is followed later by an influx of CTL also possessing LGL morphology. The CTL/LGL response in the liver is significantly greater during hepatotropic virus infections, even when a strong CTL response in the spleen is lacking.

scholarly journals Interleukin-15 promotes the growth of leukemic cells of patients with B- cell chronic lymphoproliferative disorders

Blood ◽  
1996 ◽  
Vol 87 (8) ◽  
pp. 3327-3335 ◽  
Author(s):  
L Trentin ◽  
A Cerutti ◽  
R Zambello ◽  
R Sancretta ◽  
C Tassinari ◽  
...  
Keyword(s):  
B Cells ◽  
B Cell ◽  
B Lymphocytes ◽  
Nk Cell ◽  
Lymphoproliferative Disorders ◽  
Lymphocytic Leukemia ◽  
Leukemic Cells ◽  
Interleukin 15

The recently discovered cytokine, interleukin-15 (IL-15), has been demonstrated to share several biologic properties with IL-2 in different cell systems, including T-cell and natural killer (NK) cell compartments. As for B lymphocytes, IL-15 has been shown to provide stimulatory activities in normal preactivated B cells that are mainly transduced through IL- 2 receptor (IL-2R) complex components. Since leukemic B cells from patients with chronic lymphoproliferative disorders (CLD) bear IL-2R and grow in response to IL-2, we investigated whether IL-15 triggers the proliferation of malignant B cells obtained from 12 patients with B-cell chronic lymphocytic leukemia (B-CLL) and five patients with hairy cell leukemia (HCL). Enriched B cells recovered from five healthy subjects were also studied as controls. IL-15 stimulated the proliferation of freshly isolated leukemic B cells, but not resting normal B lymphocytes, the latter being able to grow in the presence of IL-15 only after in vitro preactivation with phorbol myristate acetate. The proliferation elicited by IL-2 on leukemic cells was comparable to that determined by IL-15. Following addition of graded concentrations of IL-15 to low/intermediate-dose IL-2, resting leukemic B cells showed a higher stimulatory rate than that observed using the two cytokines separately. In normal resting B lymphocytes, this cumulative effect was not observed. The role of different IL-2R subunits in IL-15-driven growth of malignant B cells was investigated both by their expression on leukemic cells and by the block of different IL-2R subunits (p55, p75, and p64) with specific monoclonal antibodies (MoAbs). Using flow cytometry and reverse transcriptase-polymerase chain reaction (RT-PCR) analyses we demonstrated that both B-CLL and HCL leukemic B cells express the beta and gamma chains of the IL-2R system. The stimulatory activity achieved by IL-15 decreased significantly, blocking the beta and gamma chains of the IL-2R. Taken together, these findings demonstrate that IL-15 triggers the growth of leukemic B cells through IL-2R system subunits, pointing to the role of this novel cytokine in regulating the neoplastic proliferation in CLD.

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