STAT3 Activation and Oncogenesis in Lymphoma

Zhu, Fen; Wang, Kevin Boyang; Li, Rui

doi:10.3390/cancers12010019

Cited by 62 publications

(50 citation statements)

References 144 publications

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“…The role of PRL in apoptosis inhibition in cells of the immune system such as thymocytes [ 25 ] and T cells [ 26 ], and during B cell maturation in the BM [ 27 ], as well as in breast [ 26 ] and ovarian [ 28 ] cancer cells has been previously documented. Moreover, somatic gain-of-function STAT3 mutations are exclusive to T, NK, and B cell malignancies [ 29 ]. We have also documented the ability of PRL to rescue the immature B cells and WEHI-231 cell line from BCR cross-linking-induced apoptosis [ 12 ], which is an experimental scheme that mirrors the elimination of self-reactive clones and has been extensively studied as a model of B cell tolerance (clonal deletion).…”

Section: Discussionmentioning

confidence: 99%

Prolactin Rescues Immature B Cells from Apoptosis-Induced BCR-Aggregation through STAT3, Bcl2a1a, Bcl2l2, and Birc5 in Lupus-Prone MRL/lpr Mice

Flores-Fernández

Aponte-López

Suárez-Arriaga

et al. 2021

Cells

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Self-reactive immature B cells are eliminated through apoptosis by tolerance mechanisms, failing to eliminate these cells results in autoimmune diseases. Prolactin is known to rescue immature B cells from B cell receptor engagement-induced apoptosis in lupus-prone mice. The objective of this study was to characterize in vitro prolactin signaling in immature B cells, using sorting, PCR array, RT-PCR, flow cytometry, and chromatin immunoprecipitation. We found that all B cell maturation stages in bone marrow express the prolactin receptor long isoform, in both wild-type and MRL/lpr mice, but its expression increased only in the immature B cells of the latter, particularly at the onset of lupus. In these cells, activation of the prolactin receptor promoted STAT3 phosphorylation and upregulation of the antiapoptotic Bcl2a1a, Bcl2l2, and Birc5 genes. STAT3 binding to the promoter region of these genes was confirmed through chromatin immunoprecipitation. Furthermore, inhibitors of prolactin signaling and STAT3 activation abolished the prolactin rescue of self-engaged MRL/lpr immature B cells. These results support a mechanism in which prolactin participates in the emergence of lupus through the rescue of self-reactive immature B cell clones from central tolerance clonal deletion through the activation of STAT3 and transcriptional regulation of a complex network of genes related to apoptosis resistance.

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Section: Discussionmentioning

confidence: 99%

Prolactin Rescues Immature B Cells from Apoptosis-Induced BCR-Aggregation through STAT3, Bcl2a1a, Bcl2l2, and Birc5 in Lupus-Prone MRL/lpr Mice

Flores-Fernández

Aponte-López

Suárez-Arriaga

et al. 2021

Cells

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“…Considering that a specific therapy is still missing in LGLL and that current immunosuppressive drugs do not provide satisfying responses, the above-mentioned clinical impact of STAT signaling in LGLL makes these molecules attractive new targets for drug development. Several direct STAT inhibitors interacting with protein domains are available, including Stattic, S3I-201, STA-21 for STAT3 (54) and Pimozide, Stafib2, and Cpd17f for STAT5b (55). However, these compounds induce several off-targets toxicities and severe side-effects that for the time being prevent their use in the clinical setting.…”

Section: The Clinical Impact Of Stat3 and Stat5b Mutationsmentioning

confidence: 99%

Insights Into Genetic Landscape of Large Granular Lymphocyte Leukemia

et al. 2020

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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.

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“…Differences in drug targets and efficacy aside, these observations are not entirely surprising, given our emerging understanding of the importance of JAK-STAT signalling in both immune regulation and cancer progression, reviewed within this issue [ 17 ]. This issue also includes timely reviews on TYK2 in tumour immunosurveillance [ 18 ], the on the role of STAT3 in T and NK cell lymphomas [ 19 ], and its involvement in tumour evasion through elevated expression of PD-L1 [ 20 ]. STAT3 signalling in CD103 + conventional dendritic cells also provides an important immunosuppressive function via IL-10 activation.…”

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confidence: 99%