Dysfunction of immune system in the development of large granular lymphocyte leukemia

Sun, Houfang; Wei, Sheng; Yang, Lili

doi:10.1080/10245332.2018.1535294

Cited by 20 publications

(18 citation statements)

References 102 publications

(195 reference statements)

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“…LGLL and all other T/NK-lineage LGLL here studied. In addition, we also demonstrate for the first time that in most LGLL subtypes, STAT3 mutations are associated not only with a more marked neutropenia (as also has been reported by other authors in TCD8 + -LGLL and CLPD-NK) [7,9,20,30,34], but also with overall reduced counts of major normal residual populations of immune cells in blood, independently of the number of coexisting LGL clones.…”

Section: Discussionsupporting

confidence: 86%

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

Muñoz-García

Jara‐Acevedo

Caldas

et al. 2020

Cancers

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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.

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Section: Discussionsupporting

confidence: 86%

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

Muñoz-García

Jara‐Acevedo

Caldas

et al. 2020

Cancers

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“…With the recent development of targeted and immunotherapy, a number of ongoing studies aim to produce novel AML therapies, including conventional cytotoxic chemotherapies, genetic and epigenetic targeted therapies, and immunotherapies [3][4][5][6]. The T cell immune status of patients is an important factor related to the prognosis of leukemia [7][8][9][10][11]. Significantly, improvement in the clinical outcome of hematological malignancies was demonstrated by using immunotherapies such as CAR-T cell transfusion [12][13][14][15].…”

Section: Introductionmentioning

confidence: 99%

Increased PD-1+Tim-3+ exhausted T cells in bone marrow may influence the clinical outcome of patients with AML

Tan

Huang

et al. 2020

Biomark Res

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Background: Altered expression of T cell immune inhibitory receptors may result in immunosuppression and associate with the poor prognosis of leukemia patients in which the leukemic bone marrow (BM) microenvironment may contribute to such immunosuppression. We found higher numbers of programmed death-1 (PD-1) + exhausted T cells in peripheral blood (PB) from acute myeloid leukemia (AML) patients. To investigate the leukemic BM influence on immunosuppression, we further compared the distributions of PD-1 and T cell immunoglobulin mucin-3 (Tim-3) and the exhausted T cell phenotype in PB and BM from AML patients and characterized their relationship with clinical outcome. Methods: PB and BM samples from 15 patients with newly diagnosed AML were collected and analyzed for the expression of PD-1, Tim-3, CD244, and CD57 on CD3+, CD4+, and CD8+ T cells by multicolor flow cytometry. Results: The proportions of PD-1 + CD3+ and PD-1 + CD8+ T cells were significantly higher in BM compared with PB. Similarly, higher PD-1 + CD244 + CD3+ and PD-1 + CD244 + CD8+ T cells were found in BM, and an increased tendency for PD-1 + CD244 + CD4+ T cells was also detected in this group. In contrast, increased Tim-3 + CD4+/ Tim-3 + CD244 + CD4+ T cells were predominant in BM compared with PB, but there was no statistically significant difference in Tim-3 + CD8+ T cells. Moreover, PD-1 and Tim-3 double-positive CD3+/CD4+/CD8+ T cells were significantly increased in the BM group. In addition, a higher proportion of PD-1 + Tim-3 + CD3+ T cells in the BM and PD-1 + Tim-3 + CD4+ T cells in PB was detected in non-complete remission (NCR) compared with complete remission (CR) patients after first-cycle chemotherapy. Conclusions: Upregulation of PD-1 and Tim-3 and the exhausted phenotype of CD4+ and CD8+ T cells in the BM of AML patients may contribute to mediating the leukemic immunosuppressive microenvironment, and increased PD-1 + Tim-3+ CD8+ T cells may be related to T cell dysfunction in AML, which may influence clinical outcome.

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“…T-LGLL can harbor immunologic abnormalities such as seropositivity for rheumatoid arthritis, antinuclear antibody and antineutrophil antibody, polyclonal hypergammaglobulinemia, and circulating immune complexes [13] . Five percent of patients with T-LGLL has B cell dyscrasia, of which monoclonal gammopathy of undetermined significance is most common [14] .…”

Section: Discussionmentioning

confidence: 99%

Myasthenia Gravis and Large Granular Lymphocytic Leukemia: a rare association

Zhang

Varnadoe

Tandon

et al. 2020

Leukemia Research Reports

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Myasthenia gravis (MG) is an autoimmune neuromuscular junction disorder sometimes observed in hematologic malignancies as a paraneoplastic syndrome. T-cell Large Granular Lymphocytic Leukemia (T-LGLL) is a rare lymphoproliferative clonal frequently associated with autoimmune disorders. Here we report two patients with T-LGLL who developed MG. In both patients the MG was bulbar without generalized weakness and did not involve the thymus. The treatment of T-LGLL led to the resolution of MG symptoms and decrease in acetylcholine receptor antibody titers in both patients suggesting a causative association.

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Dysfunction of immune system in the development of large granular lymphocyte leukemia

Cited by 20 publications

References 102 publications

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

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

Increased PD-1+Tim-3+ exhausted T cells in bone marrow may influence the clinical outcome of patients with AML

Myasthenia Gravis and Large Granular Lymphocytic Leukemia: a rare association

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