STAT3 mutations and persistence of autoimmunity

Schultz, Kirk R.

doi:10.1182/blood-2013-08-521138

Cited by 6 publications

(4 citation statements)

References 9 publications

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“…In contrast, this specific group of PID patients classified as phenocopies of inborn errors of immunity [43][44][45] and characterized by germline STAT3 gain-offunction (GOF) mutations, also shows systemic autoimmune diseases associated with lymphoproliferation at the expense of clonal T-LGLs. Altogether, these findings would support the existence of underlying autoimmunity mechanisms that lead to the abnormally decreased numbers of many different myeloid-and lymphoid-cell populations reported here and in previous studies in LGLL [1,9,10,46], suggesting the potential existence of shared pathogenic mechanisms for the cytopenias observed in both STAT3-mutated PID and LGLL. Thus, most STAT3 (and also STAT5B) mutations detected in both diseases have been identified as GOF mutations that involve the SH2 binding domains of both STAT proteins either at dimerization/Sheinermen residues or at the phosphate-binding (pY) and pY+3 peptide binding pocket of the α-helix, BD loop [47].…”

Section: Discussionsupporting

confidence: 90%

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: 90%

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-mutant patients with aplastic anemia showed a trend toward better therapeutic response to immunosuppressive agents [94]. An immune-mediated myelosuppression hypothesis has been proposed in aplastic anemia and myelodysplastic syndrome suggesting that STAT3 mutations may produce persistent proliferation of cytotoxic autoimmune T-cell clones, as seen in large granular lymphocytic leukemia, which has also been associated with autoimmune phenomena [95]. Constitutive phosphorylation and activation of STATs have been demonstrated in various leukemias [96,97] including acute myelogenous leukemia [98], acute promyelocytic leukemia [99], acute lymphoblastic leukemia [100], chronic lymphocytic leukemia [101], and chronic myelogenous leukemia [102].…”

Section: Stat3 and Leukemogenesismentioning

confidence: 99%

STAT3 Inhibitors: Finding a Home in Lymphoma and Leukemia

et al. 2014

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The Janus kinase (JAK) and signal transducer and activator of transcription (STAT) pathway is an active mediator of cytokine signaling in the pathogenesis of solid and hematologic malignancies. The seven-member STAT family is composed of latent cytoplasmic transcription factors that are activated by phosphorylation intertwined in a network with activation that ultimately leads to cell proliferation. An activated kinase enzyme phosphorylates one STAT factor or more, which shuttle to the nucleus to regulate gene expression, promoting cell survival. Somatic STAT3 mutations have been recently reported in large granular lymphocytic leukemia, aplastic anemia, and myelodysplastic syndrome. Furthermore, the relationship between BCL6 and STAT3 in diffuse large B-cell lymphomas, particularly on the activated B-cell subtype, needs to be further explored. The search for therapeutic STAT3 inhibitors that abrogate the JAK/STAT pathway is currently under way. Targeting the STAT pathway, which seems to be critical in tumorigenesis, is promising for multiple malignancies including lymphoma and leukemia. In this paper, we review mechanisms of action, failures, and successes of STAT3 inhibitors. The Oncologist 2014; 19:536-544 Implications for Practice: Constitutive and transientendogenous inhibitors of STAT3 maintain pathway homeostasis in the cell.The potential use of STAT3 inhibitors in hematological malignancies is reviewed due to recent discoveries in the field.

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“…Furthermore, Jerez et al revealed that clonal expansion of STAT3-mutated CTLs, similar to LGL-like cells, can be detected in the context of AA and MDS. [134,135] They proposed that Review ARticle might be diagnostically useful and might be associated with clinical features in a small percentage of patients with acquired BMF. [135] It is still controversial whether STAT3 mutations are a contributing factor or a concomitant phenomenon in the clonal evolution of pathogenic CTLs or NK cells.…”

Section: Cytotoxic T Lymphocytesmentioning

confidence: 99%

Section: Why Does the Abnormal Attack Happen?mentioning

confidence: 99%

Acquired pure red cell aplasia: unraveling the immune pathogenesis

Liu,

Zhang,

Dong

et al. 2023

J Bio-X Res

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Acquired pure red cell aplasia (aPRCA) is a rare hematological disorder characterized by normochromic, normocytic anemia, reticulocytopenia, and the absence of erythroblasts. The pathogenesis of aPRCA has remained elusive. This review delves into the intricate web of immune mechanisms underlying the development of this enigmatic condition. By exploring immune responses, cytotoxic effects, and antibody-mediated processes, we dissect the immune-driven assault on erythroid progenitors. The classification of aPRCA, including its primary and secondary forms, is elucidated, with a particular emphasis on etiological factors such as viruses, drugs, thymoma, and large granular lymphocytic leukemia. Furthermore, we discuss the implications of cytogenetic changes in erythroid progenitors and immune cells in the pathophysiology of aPRCA. This comprehensive overview aims to shed light on the complex interplay between immune dysregulation and erythroid failure in aPRCA, offering insights that will be crucial for better understanding and treating this disease.

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STAT3 mutations and persistence of autoimmunity

Cited by 6 publications

References 9 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

STAT3 Inhibitors: Finding a Home in Lymphoma and Leukemia

Acquired pure red cell aplasia: unraveling the immune pathogenesis

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