Identification of a <i>miR-146b</i>-Fas ligand axis in the development of neutropenia in T large granular lymphocyte leukemia

Mariotti, Barbara; Calabretto, Giulia; Rossato, Marzia; Teramo, Antonella; Castellucci, Monica; Barilà, Gregorio; Leoncin, Matteo; Vicenzetto, Cristina; Facco, Monica; Semenzato, Gianpietro; Bazzoni, Flavia; Zambello, Renato

doi:10.3324/haematol.2019.225060

Cited by 30 publications

(33 citation statements)

References 37 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Increased FasL on cancer cells counterattacks immune cells, induces immune cell death, and eventually promotes cancer immune privilege [114]. In T cell large granular lymphocyte leukemia, it was found that STAT3-induced miR-146b loss led to increased FasL expression and potential neutropenia [115]. Besides, the miR-768-3p mimic treatment in NSCLC cell immensely increased FasL level but decreased Fas expression on cancer cells [116].…”

Section: The Mirnas and Tumor-mediated Immune Cell Deathmentioning

confidence: 99%

The role of cancer-derived microRNAs in cancer immune escape

et al. 2020

View full text Add to dashboard Cite

During malignant transformation, accumulated somatic mutations endow cancer cells with increased invasiveness and immunogenicity. Under selective pressure, these highly immunogenic cancer cells develop multiple strategies to evade immune attack. It has been well established that cancer cells could downregulate the expression of major histocompatibility complex, acquire alterations in interferon pathway, and upregulate the activities of immune checkpoint pathways. Besides, cancer cells secret numerous cytokines, exosomes, and microvesicles to regulate the functions and abundances of components in the tumor microenvironment including immune effector cells and professional antigen presentation cells. As the vital determinant of post-transcriptional regulation, microRNAs (miRNAs) not only participate in cancer initiation and progression but also regulate anti-cancer immune response. For instance, some miRNAs affect cancer immune surveillance and immune escape by interfering the expression of immune attack-associated molecules. A growing body of evidence indicated that cancer-derived immune modulatory miRNAs might be promising targets to counteract cancer immune escape. In this review, we summarized the role of some miRNAs in cancer immune escape and discussed their potential clinical application as treatment targets.

show abstract

Section: The Mirnas and Tumor-mediated Immune Cell Deathmentioning

confidence: 99%

The role of cancer-derived microRNAs in cancer immune escape

et al. 2020

View full text Add to dashboard Cite

show abstract

“…We hypothesized that the mechanism accounting for neutropenia development involves high levels of STAT3 activation (14). More in detail, we recently demonstrated the presence of a STAT3-miR-146b-FasL axis in neutropenic T-LGLL patients, that, once triggered, leads to high production of Fas Ligand, which in turn is responsible of neutrophil apoptosis (51). These data emphasize the role of STAT3 activation in the pathogenesis of LGLL neutropenia, with STAT3 mutations likely being involved in further boosting this mechanism.…”

Section: The Clinical Impact Of Stat3 and Stat5b Mutationsmentioning

confidence: 99%

Insights Into Genetic Landscape of Large Granular Lymphocyte Leukemia

et al. 2020

Self Cite

View full text Add to dashboard Cite

Large granular lymphocyte leukemia (LGLL) is a chronic proliferation of clonal cytotoxic lymphocytes, usually presenting with cytopenias and yet lacking a specific therapy. The disease is heterogeneous, including different subsets of patients distinguished by LGL immunophenotype (CD8+ Tαβ, CD4+ Tαβ, Tγδ, NK) and the clinical course of the disease (indolent/symptomatic/aggressive). Even if the etiology of LGLL remains elusive, evidence is accumulating on the genetic landscape driving and/or sustaining chronic LGL proliferations. The most common gain-of-function mutations identified in LGLL patients are on STAT3 and STAT5b genes, which have been recently recognized as clonal markers and were included in the 2017 WHO classification of the disease. A significant correlation between STAT3 mutations and symptomatic disease has been highlighted. At variance, STAT5b mutations could have a different clinical impact based on the immunophenotype of the mutated clone. In fact, they are regarded as the signature of an aggressive clinical course with a poor prognosis in CD8+ T-LGLL and aggressive NK cell leukemia, while they are devoid of negative prognostic significance in CD4+ T-LGLL and Tγδ LGLL. Knowing the specific distribution of STAT mutations helps identify the discrete mechanisms sustaining LGL proliferations in the corresponding disease subsets. Some patients equipped with wild type STAT genes are characterized by less frequent mutations in different genes, suggesting that other pathogenetic mechanisms are likely to be involved. In this review, we discuss how the LGLL mutational pattern allows a more precise and detailed tumor stratification, suggesting new parameters for better management of the disease and hopefully paving the way for a targeted clinical approach.

show abstract

“…Intriguingly, miR-146b resulted to be down-regulated in T-LGL of neutropenic patients, due to a hypermethylation of its promoter. Of note, a direct role of STAT3 activation was suggested in this epigenetic alteration, by promoting the DNA methyltransferase 1 (DNMT1) expression [12].…”

Section: Novel Insights In Fasl Regulation: the Stat3/mir-146b/fasl Axismentioning

confidence: 99%

“…Herein, we will discuss the putative pathogenetic hypotheses and mechanisms accounting for neutropenia development, particularly the recent identification of a microRNA(miR)-146b defective expression in leukemic T-LGL [12]. Moreover, we will focus on both current therapies and novel promising strategies for the treatment of neutropenic LGLL patients.…”

Section: Introductionmentioning

confidence: 99%

Neutropenia and Large Granular Lymphocyte Leukemia: From Pathogenesis to Therapeutic Options

Calabretto

Teramo

Barilà

et al. 2021

Cells

Self Cite

View full text Add to dashboard Cite

Large granular lymphocyte leukemia (LGLL) is a rare lymphoproliferative disorder characterized by the clonal expansion of cytotoxic T-LGL or NK cells. Chronic isolated neutropenia represents the clinical hallmark of the disease, being present in up to 80% of cases. New advances were made in the biological characterization of neutropenia in these patients, in particular STAT3 mutations and a discrete immunophenotype are now recognized as relevant features. Nevertheless, the etiology of LGLL-related neutropenia is not completely elucidated and several mechanisms, including humoral abnormalities, bone marrow infiltration/substitution and cell-mediated cytotoxicity might cooperate to its pathogenesis. As a consequence of the multifactorial nature of LGLL-related neutropenia, a targeted therapeutic approach for neutropenic patients has not been developed yet; moreover, specific guidelines based on prospective trials are still lacking, thus making the treatment of this disorder a complex and challenging task. Immunosuppressive therapy represents the current, although poorly effective, therapeutic strategy. The recent identification of a STAT3-mediated miR-146b down-regulation in neutropenic T-LGLL patients emphasized the pathogenetic role of STAT3 activation in neutropenia development. Accordingly, JAK/STAT3 axis inhibition and miR-146b restoration might represent tempting strategies and should be prospectively evaluated for the treatment of neutropenic LGLL patients.

show abstract

Identification of a miR-146b-Fas ligand axis in the development of neutropenia in T large granular lymphocyte leukemia

Abstract: wordsMain text: 3380 words

Cited by 30 publications

References 37 publications

The role of cancer-derived microRNAs in cancer immune escape

The role of cancer-derived microRNAs in cancer immune escape

Insights Into Genetic Landscape of Large Granular Lymphocyte Leukemia

Neutropenia and Large Granular Lymphocyte Leukemia: From Pathogenesis to Therapeutic Options

Contact Info

Product

Resources

About